Download Tumours of the Heart

CHAPTER 4
Tumours of the Heart
Although tumours of the heart do not contribute significantly to
the overall tumour burden, they may cause a variety of cardiac
and systemic symptoms. Clinical features depend not only on
the size, but, to a significant extent, on the anatomic location.
Small, benign neoplasms may have devastating clinical consequences if in a critical location.
Progress in imaging and cardiac surgery have considerably
improved the prognosis. However, cardiac sarcomas are still
life-threatening diseases.
Due to the low frequency, there is no specific garding scheme
for malignant heart tumours. This volume largely follows the
principles of classification and grading detailed in the WHO
Classification of Tumours of Soft Tissue and Bone.
WHO histological classification of tumours of the heart
Benign tumours and tumour-like lesions
Rhabdomyoma
Histiocytoid cardiomyopathy
Hamartoma of mature cardiac myocytes
Adult Cellular Rhabdomyoma
Cardiac myxoma
Papillary fibroelastoma
Haemangioma
Cardiac fibroma
Inflammatory myofibroblastic tumor
Lipoma
Cystic tumour of the atrioventricular node
8900/0
8904/0
8840/0
9120/0
8810/0
8825/1
8850/0
Malignant tumours
Angiosarcoma
Epithelioid haemangioendothelioma
Malignant pleomorphic fibrous histiocytoma
(MFH)/Undifferenciated pleomorphic sarcoma
Fibrosarcoma and myxoid fibrosarcoma
Rhabdomyosarcoma
Leiomyosarcoma
Synovial sarcoma
Liposarcoma
Cardiac lymphomas
Metastatic tumours
Pericardial tumours
Solitary fibrous tumour
Malignant mesothelioma
Germ cell tumours
Metastatic pericardial tumours
9120/3
9133/3
8830/3
8840/3
8900/3
8890/3
9040/3
8854/3
8815/1
9050/3
__________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {6} and the Systematized Nomenclature of Medicine (http://snomed.org).
Behaviour is coded /0 for benign tumours, /3 for malignant tumours, and /1 for borderline or uncertain behaviour.
250 Tumours of the heart
Tumours of the heart: Introduction
Epidemiology
The estimated frequency of cardiac
tumours ranges from 0.0017-0.33%
{2165}. In a review of 22 autopsy-based
series of primary cardiac tumours a frequency of 0.021% was identified among
731,309 patients {1656}. In one 20-year
(1972-1991) review of 12,485 autopsy
cases, there was a 0.056% incidence of
primary tumours and a 1.23% incidence
of secondary tumours {1116}. However,
these data may have a high referral bias
and may not reflect population-based
incidence rates {2079}. At the Mayo
Clinic, the autopsy incidence of primary
cardiac tumours from 1915 to 1931 was
0.05%, but more than tripled to 0.17%
between 1954 and 1970 {2165}; again,
referral bias may have played a role in
this change.
When most cardiac tumours were diagnosed at autopsy, myxomas and sarcomas were reported at a similar frequency.
With the utilization of cardiopulmonary
bypass and surgical excision, the reported frequency of myxomas as opposed to
cardiac sarcomas has increased substantially {249,1568}. In a review of surgical series, cardiac myxomas constitute
77% of surgically excised tumours, and
cardiac sarcomas, 10% {249}.
In children, cardiac tumours are not common and most are benign {249}. The
most common pediatric tumours include
rhabdomyomas, fibromas, myxomas,
and teratomas {249,356}.
Secondary cardiac tumours, either
metastatic or by direct invasion, outnumber primary cardiac neoplasms {1116}. A
review of 3,314 autopsies found a 2.9%
frequency of metastatic tumours involving the heart {12}. The most common primary sites are lung, breast, and cutaneous melanoma.
Clinical features
Cardiac neoplasms may cause a variety
of signs and symptoms {1225,1791,
2079}. The clinical presentation depends
on the size of the tumour and its anatomic location. Growth rate, friability, and
invasiveness are also important factors
that determine clinical features {737}.
Large tumours may be relatively silent,
whereas small tumours in a critical location may give rise to devastating clinic
consequences.
Left atrial tumours, especially those that
are mobile or pedunculated, may lead to
systemic embolism involving the coronary, cerebral and peripheral circulations
{737,1568,2077}, resulting in myocardial
infarction, stroke or ischemic viscera or
limbs. Left atrial tumours may also interfere with mitral valve function resulting in
mitral stenosis or regurgitation. Cardiac
murmurs and a characteristic tumour
“plop” may be auscultated. Valve dysfunction manifests as left-sided heart failure with shortness of breath, orthopnea,
paroxysmal nocturnal dyspnoea, pulmonary edema, fatigue, cough, and
chest pain {356}.
Intramural left ventricular tumours may
be asymptomatic or present with a mass
effect. With protrusion into the cavity,
hemodynamic compromise may result
{1225}. Local extension of the tumour
may cause conduction or coronary artery
compromise with chest pain, myocardial
infarction, arrhythmia, heart block or sudden death {356,737,1225,1791}.
Right atrial or right ventricular tumours
may result in right heart failure from atrioventricular or pulmonary outflow
obstruction, resulting in peripheral
edema, hepatomegaly, ascites, shortness of breath, syncope and sometimes,
sudden death {737}. If the tumours interfere with valve function they may result in
regurgitation or stenosis {1791}.
Right-sided cardiac tumours may
embolize to the lungs and present as pulmonary emboli with chest pain, pulmonary infarction and haemoptysis
{1634,1791}. Chronic embolization may
also mimic chronic thromboembolic disease with signs and symptoms of pulmonary hypertension.
Pericardial tumours may cause chest
pain typical of pericarditis {1225,1568}.
The tumours may be haemorrhagic and
cause pericardial effusion and tamponade {1634}. However, constrictive peri-
A.P. Burke
J.P. Veinot
R. Loire
R. Virmani
H. Tazelaar
H. Kamiya
P.A. Araoz
G. Watanabe
carditis may also result from tumour infiltration.
Rarely, tumours such as myxoma, cause
systemic symptoms, including anorexia,
weight loss, fatigue and malaise which
may mimic a variety of systemic disorders {356,737,1774,2077}. Interestingly,
they may also cause haematologic
abnormalities, including anemia, polycythemia, leukocytosis, thrombocytosis
and elevated sedimentation rate {1225}.
Tumour production of mediators, including interleukins, has been reported
{1774}.
Imaging
Primary tumours of the heart and pericardium may be detected as an abnormal finding on a chest radiogram or
another imaging test obtained for an
unrelated reason. Once detected cardiac imaging is needed to define (1)
tumour location, extent and boundaries;
(2) relationships with adjacent key cardiac structures such as valves and coronary arteries; (3) tumour type; and (4)
presence and degree of functional
impairment. The main non-invasive imaging modalities for evaluating primary cardiac tumours each have advantages and
disadvantages. They are often used
together in a complementary manner for
diagnosis and surgical planning.
Echocardiography
The primary advantage of echocardiography is that it has the best spatial and
temporal resolution and provides excellent anatomic and functional information
{492,705,1070,1162,2104,2215}. It is the
optimal imaging modality for small masses (<1 cm) or masses arising from
valves. A second major advantage of
echocardiography is the ability to image
velocities with Doppler, which allows for
assessment of presence, degree, and
location of obstructions to blood flow or
valve regurgitation. Echocardiography is
typically the modality used for the initial
evaluation of cardiac tumours and may
be the only diagnostic test required in
some patients. Disadvantages include
Introduction 251
suboptimal image quality in patients with
poor acoustic windows, inability to image
extent of disease outside of the mediastinum, and relatively low soft tissue
contrast, which limits detection of tumour
infiltration and characterization of tumour
tissue. Also, intravenous contrast agents
are not routinely used with echocardiography, which limits the ability to characterize tumour vascularity.
Magnetic Resonance Imaging (MRI)
The primary advantage of MRI is its
excellent soft tissue contrast which
makes it the most sensitive modality for
detection of tumour infiltration. MRI has
more manipulable imaging parameters
than other imaging modalities. Because
of this, MRI is the best modality for characterizing tumour tissue {1003,1768,
1831,2156}. For example, a T2-weighted
standard or fast spin echo sequence distinguishes tumours with high water content, such as haemangioma, from
tumours with low water content, such as
fibroma. A third advantage of MRI is the
ability to characterize tumour vascularity
with intravenous contrast. Though not as
flexible as echocardiography, MRI does
allow assessment of wall motion and
assessment of velocities through large
vessels. This allows for characterization
of ventricular function, inflow or outflow
obstruction and valve regurgitation. The
primary disadvantage of MRI is long
examination times, which translates into
the need for sedation in children, and the
need for reliable ECG gating. MRI should
be considered when the tissue type,
exact location, or the relationships of the
tumour with neighbouring structures are
not completely defined by echocardiography or when surgical resection of the
tumour is considered.
Computed Tomography (CT)
ECG gated CT scans with the latest generation of multidetector scanners or with
electron beam scanners are also very
useful for cardiac imaging {65,275}. In
many ways, the advantages and disadvantages of CT are intermediate between
those of echocardiography and MRI.
Modern CT scanners have excellent spatial resolution, which is better than that of
MRI, but not as high echocardiograpy.
CT has better soft tissue contrast than
echocardiography, and can be used to
definitively characterize fatty content and
calcifications; however, the overall soft
252 Tumours of the heart
Fig. 4.01
Parameters of the grading system for sarcomas of
the Féderation Nationale des Centres de Lutte
Contre le Cancer (FNCLCC).
Tumour differentiation
Score 1: Sarcomas closely resembling
normal adult mesenchymal tissue
(e.g., low-grade leiomyosarcoma).
Score 2: Sarcomas for which histological
typing is certain (e.g., Myxoid
Fibrosarcoma)
Score 3: Undifferentiated, angiosarcoma
Mitotic count
Score 1: 0-9 mitoses per 10 HPF*
Score 2: 10-19 mitoses per 10 HPF
Score 3: ≥20 mitoses per 10 HPF
Tumour necrosis
Score 0: No necrosis
Score 1: <50% tumour necrosis
Score 2: ≥50% tumour necrosis
Histologic grade
Grade 1: Total score 2,3
Grade 2: Total score 4,5
Grade 3: Total score 6, 7, 8
Modified from Trojani et al {2031}.
*A high-power field (hpf) measures 0.1734mm2
tissue contrast and ability to characterize
tumour infiltration and tumour type is less
than that of MRI. Intravenous contrast
can provide information about tumour
vascularity, an advantage CT shares with
MRI. CT may be used as an adjunct to
both echocardiography and MRI.
Cardiac Catheterization
This is seldom required for diagnosis of
cardiac tumours, but may be performed
in adults to exclude coronary artery disease. Angiography provides indirect and
nonspecific imaging based on filling
defects within the cardiac chambers and
displacement of the coronary arteries
{347,1840}. Two exceptions are worth
noting. First, endomyocardial biopsy for
tissue typing may be considered in
selected patients. Second, selective
coronary angiography is helpful when
planning surgical resection of an
intramyocardial tumour.
Tumour grading and staging
Given the low frequency of malignant
cardiac tumours, there is no grading
scheme specifically referring to malignant heart tumours. This volume uses the
criteria published in the recent WHO
Classification of Tumours of Soft Tissue
and Bone {590}. The concept of grading
sarcomas was first introduced in 1977
{1712}. Several grading systems have
since been proposed which have shown
to correlate with prognosis {412,1247,
1418,2031,2070}. The two most important parameters in non-cardiac soft tissue seem to be the mitotic index and
extent of tumour necrosis {1793,2031,
2070}. Most pathologists recognize three
grades of malignancy: G1, low grade;
G2, intermediate grade; and G3, high
grade. Some use a 4-tiered system.
The two most widely used systems are
those of the NCI (U.S. National Cancer
Institute) {412,413} and the FNCLCC
(Fédération Nationale des Centres de
Lutte Contre le Cancer) {387-389,748,
2031}.
According to the methodology defined in
1984 {412} and refined in 1999 {413}, the
NCI system uses a combination of histologic type, cellularity, pleomorphism and
mitotic rate for attributing grade 1 or 3.
All the other types of sarcomas are classified as either grade 2 or grade 3
depending on the amount of tumour
necrosis, with 15% necrosis as the
threshold for separation of grade 2 and
grade 3 lesions.
The FNCLCC system is based on a score
obtained by evaluating three features:
tumour differentiation, mitotic rate and
amount of tumour necrosis {2031}. A
score is attributed independently to each
parameter and the grade is obtained by
adding the three attributed scores.
Tumour differentiation is highly dependent on histologic type and subtype. The
reproducibility of this system has been
tested by 15 pathologists: the crude proportion of agreement was 75% for tumour
grade, but only 61% for histologic type
{748}.
Because of the limitations and pitfalls of
grading, the following guidelines have
been suggested to improve reliablility:
> Grading should be used only for
untreated primary soft tissue sarcomas.
> Grading should be performed on representative and well-processed material.
> Grading is not a substitute for a histologic diagnosis and does not differentiate
benign and malignant lesions. Before
grading a soft tissue lesion, one must be
sure that one is dealing with a true sarcoma and not a pseudosarcoma.
> Parameters of grading must be carefully
evaluated, particularly the mitotic rate.
The WHO Classification of Tumuors of
Soft Tissue and Bone {590} offers additional information on the grading of soft
tissue sarcomas.There is no TNM classification for cardiac malignancies.
Treatment and prognosis
In general, surgical resection, when possible, is the treatment of choice for primary cardiac tumours in symptomatic
patients. It is also highly desirable for
patients whose tumours are identified
incidentally because of the ever-present
risk of sudden death, embolism, obstruction, or arrhythmia {307,952}. In patients
with rhabdomyomas and so called histiocytoid cardiomyopathy, predominantly
children, there are some who suggest
that surgical intervention is only necessary in the face of life-threatening symptoms, as these tumours are benign and
known to regress with age {1880}.
Surgical strategy varies by tumour type.
Cardiac myxomas arise mainly from the
left atrial septum, and the surgical strategy usually includes complete tumour
resection
with
underlying
stalk.
Sometimes reconstruction using a prosthetic patch is necessary {952}. The
prognosis of patients with cardiac myxomas is excellent. They may occasionally
recur, especially in patients with Carney
complex, an autosomal dominant syndrome characterized by associated skin
lesions, endocrine abnormalities and
other unusual tumours {1018}. It is difficult to suggest a regular surgical strategy for other cardiac tumours as they
arise in various locations. The prognosis
for other benign tumours is generally
favourable with low recurrence, and it is
quite good even if incompletely excised
{307,952,1880}. Orthotopic heart transplantation is an option if tumour resection
and reconstruction would be expected to
cause irreparable damage to essential
cardiac structures {731}.
For malignant cardiac tumours, complete
resection is often impossible because of
local spread {2071}. The prognosis of
patients with primary malignant cardiac
tumours is very poor even if complete resection is attempted {952,2071}. Adjuvant
chemotherapy and irradiation are usually
also given, but these are not effective in
most cases {2071}. Favourable results of
heart transplantation for primary malignant cardiac tumours have been reported
despite immunosuppression {731,733,
1962, 2071}.
Introduction 253
Benign tumours with myocyte
differentiation
B.M. Shehata
A.P. Burke
H. Tazelaar
C.R. Patel
Rhabdomyoma
be identified as early as 21 weeks by
ultrasound {863}. The tumours may
cause infant respiratory distress, congestive heart failure, or low cardiac output. Right-sided tumours that cause
obstruction may cause cyanosis, or features suggestive of tetralogy of Fallot or
pulmonary stenosis {41,583}. Left-sided
tumours may present as subaortic
obstruction, or hypoplastic left heart syndrome {2068}. Rarely they can be associated with structural cardiac defects
{2113}. Patients with “rhabdomyomatosis” or diffuse microscopic involvement
of the myocardium may present as
though they have a cardiomyopathy.
Spontaneous regression is a common
feature {1254,1840}.
Electrocardiographic abnormalities will
vary depending on location, but evidence of ventricular hypertrophy and STT wave abnormalities consistent with
ischemia and/or strain are common. The
conduction abnormalities consist of bundle branch block, preexcitation, and first
to third degree atrioventricular block.
Definition
A benign tumour of the cardiac myocyte,
which can be solitary or multiple. The
cells typically contain large glycogen
filled vacuoles.
ICD-O code
8900/0
Epidemiology
Cardiac rhabdomyoma is commonly
associated with tuberous sclerosis, an
autosomal dominant disorder with a high
mutation rate. It involves multiple organs
including brain, kidney, pancreas, retina
and skin. In autopsy series, patients with
tuberous sclerosis have a 30% incidence
of
cardiac
rhabdomyoma
{571}.
However, the actual incidence is likely
higher since series that have evaluated
patients with echocardiography have
found an incidence between 40% and
86% {119,492,777}. The presence of
multiple cardiac rhabdomyomas prenatally may be the earliest manifestation of
tuberous sclerosis.
Localization
Rhabdomyomas are firm, white, well-circumscribed lobulated nodules that occur
A
in any location in the heart, but are more
common in the ventricles. In patients with
tuberous sclerosis, tumours are usually
multiple (> 90%) and can consist of
numerous miliary nodules measuring less
than 1 mm; in this instance, the term
“rhabdomyomatosis” has been used. The
most common locations are the left ventricle and ventricular septum, although
30% will have atrial wall or right ventricular involvement {1602}. In contrast to
patients with tuberous sclerosis, approximately 50% of sporadic rhabdomyomas
occur singley.
Clinical features
Signs and symptoms
Rhabdomyomas are the most common
tumours in the pediatric age group. They
are also the tumours most commonly
diagnosed during the prenatal period by
foetal echocardiography. Intrauterine as
well as sudden death after birth has
been attributed to these tumours.
Clinical and hemodynamic findings are
related to the number, position, and size
of the tumours. For instance large intramural or intracavitary tumours may
obstruct valvular orifices, or occlude
intracavitory spaces {1254}. Foetal dysrhythmias or non-immune hydrops may
B
Fig. 4.01 Rhabdomyoma. A Echocardiogram of an infant who presented with supraventricular tachycardia.
There are multiple rhabdomyomas. These eventually regressed and the arrhythmias resolved.
B Echocardiographic imaging from the apical chamber view, showing multiple cardiac rhabdomyomas
involving the left (LV) and right (RV) ventricles.
254 Tumours of the heart - Benign tumours with myocyte differentiation
R. Virmani
T. Geva
G. Tornambene
D.J. Radford
Imaging
At echocardiography rhabdomyomas
appear as homogeneous, well-circumscribed echogenic masses in the ventricular myocardium, possibly protruding
into the ventricular cavity. Although
uncommon, extensive rhabdomyomas
can be associated with ventricular dysfunction. Given that the finding of multiple cardiac masses is diagnostic of rhabdomyoma, especially in patients with
tuberous sclerosis, and that the tumours
are not infiltrative, echocardiography
usually provides adequate information
for diagnosis and clinical management. If
there is question of tumour type or of
tumour invasion, MRI or CT may be used
to further define the tumours. At MRI,
rhabdomyomas appear as well-circumscribed masses with signal characteristics similar to that of normal myocardium
{155,737,1003}. Compared with the signal from uninvolved myocardium, the
masses are hypointense on postgadolinium imaging. At CT, rhabdomy-
with sparse myofilaments. There is a
strong reaction with periodic acid-Schiff
reagent, reflecting the presence of abundant intracellular glycogen.
A
C
B
D
Fig. 4.02 Cardiac rhabdomyoma. A Multiple rhabdomyomas in an infant with tuberous sclerosis complex
(courtesy of William D. Edwards, M.D.). B Intraoperative photograph. The tumour nearly fills the ventricular cavity, and is glistening and polypoid. C Stillborn child with a ventricular rhabdomyoma. D Subaortic
rhabdomyoma in an 5 months old child.
omas also appear as multiple nodules,
which may be hyper or hypoattenuating
compared to normal myocardium. With
MRI or CT, the rest of the body can be
imaged for signs of tuberous sclerosis.
However, because rhabdomyoma has
many imaging features similar to normal
myocardium, echocardiography, MRI,
and CT may be complementary as rhabdomyomas that are not visible by one
modality may be visible on another {737}.
Macroscopy
Single or multiple, they are well-circumscribed, non-capsulated white or grey
white nodules which may vary in size
from millimeters to several centimeters.
Tumours can become quite large, espe-
A
cially in sporadic cases. In one series of
14 cases, the range was 0.3-9.0 cm, with
a mean of 3.4 cm {248}. They most often
occur in the ventricle, but can be found
in the atria, at the cavoatrial junction and
on the epicardial surface. Large tumours
may obliterate and distort a ventricular
cavity.
Histopathology
Cardiac rhabdomyomas are well-demarcated nodules of enlarged cardiac
myocytes with cleared cytoplasm. In
some cells, strands of eosinophilic cytoplasm stretch from a central nucleus to
the cell membrane giving rise to cells
that resemble a spider (“spider cells”).
The majority of cells show vacuolization
Immunoprofile
Immunohistochemical studies document
the striated muscle characteristics of
rhabdomyoma cells, which express myoglobin, desmin, actin, and vimentin.
Tumour cells do not express cell proliferation markers such as Ki-67 and PCNA,
indicating that the lesions are more likely
hamartomas as opposed to neoplasms
{248}.
Electron microscopy
By electron microscopy, the cells resemble altered myocytes. They possess
abundant glycogen, small and sparse
mitochondria, and cellular junctions
resembling intercalated disks surround
the cell periphery. In contrast, the intercalated disks of differentiated myocytes
are located exclusively at the poles of the
cell. Intercalated discs and myofibrils or
collections of Z band material are present. Rarely one may observe there primitive T-tubules. Leptomeric fibers close to
the sarcolemma may also be identified.
Differential diagnosis
The diagnosis of cardiac rhabdomyoma
in infants and young children is straightforward. In patients with multiple non-calcifying masses, especially with other
manifestations of tuberous sclerosis
complex, a tissue diagnosis is unnecessary. However, because the tumours
have been shown to regress with age
and multiple biopsies do not allow for
evaluation of the morphologic changes
that characterize this process, the relationship between persistent rhabdomyomas and so-called adult rhabdomy-
B
Fig. 4.03 Rhabdomyoma. A The subendocardium shows a poorly demarcated area of cellular vacuolization.
B A higher magnification note "spider" cells, several vacuolated tumor cells, and cells with abundant
eosinophilic cytoplasm , which is more typical for rhabdomyomas in older children.
Fig. 4.04 Cardiac rhabdomyoma with classic spider
cell.
Rhabdomyoma 255
omas and hamartomas is not clear. In the
rare examples of rhabdomyomas in older
children, there is often a paucity of spider
cells, resulting in a tumour with some
characteristics of adult rhabdomyomas,
but without the proliferative activity.
Hamartoma of mature cardiac myocytes,
which, like rhabdomyoma, is a non-proliferative hamartomatous lesion, occurs in
adults. These tumours lack circumscription and spider cells.
Genetic alterations
The familial form of tuberous sclerosis,
which is present in up to 50% of patients
with cardiac rhabdomyoma, exhibits
autosomal dominant inheritance. Two
disease genes have been identified:
TSC-1 at chromosome 9q34, and TSC-2
at chromosome 16p13 {1613}. The TSC1 gene encodes hamartin, and TSC-2
tuberin, proteins involved in tumour suppression. Loss of heterozygosity is often
found at these loci in tumours from
patients with tuberous sclerosis. The precise roles of TSC-1 and TSC-2 in the
development of cardiac tumours and
regulation of embryonic and neonatal
cardiomyocyte growth remain to be elucidated.
Treatment and Prognosis
Rhabdomyomas have a natural history of
spontaneous regression {204,556,1840}.
However, serious symptoms may precipitate the need for surgical resection.
When arrhythmias are the presenting
symptom, treatment with anti-arrhythmic
drugs is commenced. If control is
achieved by that means, then drugs can
A
be continued until the arrhythmias or
tumours regress. If drugs fail to control
arrhythmias, surgical resection is indicated. When a tumour is causing intracardiac obstruction, surgery is necessary
{180,525,538,1289}.
Histiocytoid cardiomyopathy
Definition
Histiocytoid cardiomyopathy is a rare,
but distinctive arrhythmogenic disorder
caused by a neoplastic or hamartomatous proliferation of cardiac cells with
some Purkinje cell characteristics.
Synonyms
Purkinje cell hamartoma, arachnocytosis
of the myocardium, infantile cardiomyopathy, infantile xanthomatous cardiomyopathy, oncocytic cardiomyopathy,
focal lipid cardiomyopathy, isolated cardiac lipidosis, infantile cardiomyopathy
with histiocytoid changes, myocardial or
conduction system hamartoma, foamy
myocardial transformation, and congenital cardiomyopathy.
Epidemiology
Histiocytoid cardiomyopathy occurs predominantly in the first two years of life;
20% of cases are diagnosed in the first
month, 60% in the first year, and less
than 3% after two years of life. The prevalence of this disease may be higher than
the reported cases would suggest, since
some cases are undoubtedly diagnosed
as Sudden Infant Death Syndrome
(SIDS).
The female preponderance is 3:1. In
approximately 5% of cases there seems
to be a familial tendency.
Clinical features
Histiocytoid cardiomyopathy is an
arrhythmogenic disorder; 70% of published cases the patients present with a
spectrum of arrhythmias and electrical
disturbances including: paroxysmal atrial
tachycardia, atrial fibrillation, ventricular
fibrillation, ventricular tachycardia, premature atrial contractions, premature
ventricular contractions, Wolff-ParkinsonWhite syndrome, and right or left bundle
branch block.
Approximately 20% of patients present
as sudden death and often such cases
have been misclassified as Sudden
Infant Death Syndrome (SIDS). Other
infants experience flu-like symptoms preceding or accompanying the cardiac
manifestations. The majority of patients
(95%) display cardiomegaly, but may
also have a number of associated anomalies, including cardiac malformation
(16%): ventricular and atrial septal
defects, hypoplastic left heart syndrome;
and endocardial fibroelastosis. Extracardiac anomalies occur in 17% of
patients including corneal opacities,
microcephaly, cataract, aphakia, hydrocephalus, agenesis of the corpus callosum, cleft palate, laryngeal web, and linear skin defect. Combined cardiac and
extracardiac anomalies occur in 4%, and
7% show extracardiac histiocytoid cells
in exocrine and endocrine glands {1794}.
B
Fig .4.05 Histiocytoid cardiomyopathy. A Gross picture of the heart, showing multiple histiocytoid nodules in the aortic valve leaflets, endocardium, and papillary
muscles (arrows). B Macroscopic photograph of a heart demonstrating the left ventricle and portion of the mitral valve. Note pale tan endocardial nodules at the
level of the annulus.
256 Tumours of the heart - Benign tumours with myocyte differentiation
A
B
Fig. 4.06 Histiocytoid cardiomyopathy. A Discrete, circumscribed nodule of pale cells, superficially resembling foamy macrophages in the subendocardium.
B Subendocardial histiocytoid nodule. Note the ill-defined border with adjacent myocardial fibers.
Etiology
Many theories of the etiopathogenesis
have been proposed, including viral
infection, myocardial ischemia, toxic
exposure, and metabolic disorders such
as glycogen storage disease, cardiac
lipidosis, and various mitochondrial
myopathies. However, the clinical, gross,
microscopic, and ultrastructural findings
show clear differences between the
above-mentioned disorders and histiocytoid cardiomyopathy. The clinical presentation (arrhythmia), the distribution of histiocytoid cells, and their ultrastructural
and immunohistochemical characteristics, all point to the cardiac conduction
system as playing a key role. The primitive Purkinje cells of the developing heart
show a striking resemblance to histiocytoid cells. Both types of cells show strong
positivity for cholinesterase by frozen
section histochemistry and for neutral
lipids with the Sudan Black stain.
Cholinesterase is present only in the conduction tissue of the heart; it is not present in contractile myocytes {1794}.
Macroscopy
Single or multiple subendocardial yellowtan nodules or plaques ranging from 115 mm may be seen in both ventricles,
the septum, and on all four cardiac
valves. Although these nodules are mainly seen beneath the endocardium following the distribution of the bundle branches of the conduction system, they can
also be seen in the inner myocardium
and subepicardial areas. Lesions may be
grossly inapparent as nodules, but multiple cross sections of the myocardium
may show a mottled appearance with
irregular ill-defined yellowish-tan areas.
able size, scattered desmosomes, intercalated discs, and leptometric fibers.
Histopathology
Histiocytoid cardiomyopathy lesions
appear as multifocal, ill-defined islands
of large polygonal cells with granular
eosinophilic cytoplasm, small round to
oval shaped nuclei containing occasional nucleoli. The cytoplasmic appearance
is due to extensive accumulation of mitochondria. The cells are distributed along
the bundle branches of the conduction
system. The sinoatrial and atrioventricular nodes are involved in 28% of cases;
however, these areas are not sampled
routinely {1794}.
Immunoprofile
Histiocytoid cardiomyopathy cells react
with anribodies to desmin, myoglobin,
myosin, and muscle specific actin. There
is no expression of macrophage or histiocyte antigens (CD68, CD69, MAC 387,
LN3, HAM-56). The cells also fail to react
with antibodies to vimentin and cytokeratin (CAM-5.2), whereas S-100 protein
reactivity is variable. Cell proliferation
markers (Ki-67 and MIB-1) are usually
negative {682,1713}.
Differential diagnosis
The disease has been confused with mitochondrial cardiomyopathy. However, there
are major gross, light microscopic, and
ultrastructural differences between the two
diseases. Mitochondrial cardiomyopathy
shows no discrete nodules as present in
histiocytoid cardiomyopathy. Additionally,
in mitochondrial cardiomyopathy, all
myocytes are affected, but to a variable
degree, whereas in histiocytoid cardiomyopathy, only focal areas of the heart are
involved, but the affected cells are affected totally. The ultrastructural changes in
histiocytoid cardiomyopathy cells consist
of increased numbers of mitochondria with
and without structural changes and
reduced myofibrils. In mitochondrial cardiomyopathy, the mitochondria are consistently abnormal in a varitey of ways. They
are enlarged, show variation in size and
shape, contain occasional glycogen particles, and have cristae which are
increased in number and on cross section,
are arranged in a concentric circular fashion (like growth rings of a tree) surrounding
occasional dense bodies.
Electron microscopy
Ultrastructurally, the cells of histiocytoid
cardiomyopathy show poorly developed
intercellular junctions. Their cytoplasm
contains a superabundance of swollen
mitochondria with disorganized cristae
and dense membrane bounded granules, which push the diminished myofibrils to the periphery of the cell. The cytoplasm also contains lipid droplets of vari-
Genetic susceptibility
Familial recurrence of histiocytoid cardiomyopathy in 5% of cases has led to
several proposals of a genetic mechanism. The female preponderance of
cases suggests an X-linked mutation
causing prenatal lethality in the homozygous male {168,234,1898}. A female
infant with “oncocytic cardiomyopathy”
and microphthalmia with linear skin
Histiocytoid cardiomyopathy 257
defects showed monosomy for Xp22
{1543}. Biochemical {1543} and molecular (mitochondrial DNA) {57} evidence
suggest a defect of complex III (reduced
coenzyme Q-cytochrome c reductase) of
the respiratory chain in cardiac mitochondria. Such a mechanism could be
responsible for the mitochondrial
changes observed by light and electron
microscopy, and the systemic involvement in some patients. It has been suggested that the disease is due to a mutation in Sox6 gene (p100H), which is associated with widespread myopathies
{385}. From reported cases with known
ethnic background, histiocytoid cardiomyopathy appears to be more common in Caucasian (80%) followed by
African-American (15%), and LatinAmerican infants (3%); it is rare in Asian
infants {1794}.
Prognosis and predictive factors
Histiocytoid cardiomyopahty causes
incessant ventricular tachycardia in small
children and can result in sudden death.
Surgical excision or direct-vision cryoablation of the multiple small nodular
tumours is required for long-term cure
{665}. Surgical intervention, electrophysiologic mapping, and ablation of the
arrhythmogenic foci result in a survival
rate of approximately 80%. Some authors
have found that aggressive anti-arrhythmic treatment may allow the tumours to
regress without subjectiing patients to
surgery. A few patients with extensive
disease have undergone cardiac transplant {664,678,984,1286}.
Hamartoma of mature cardiac
myocytes
Definition
The term “hamartoma” has been loosely
applied to several cardiac tumours, most
commonly histiocytoid cardiomyopathy
(“Purkinje cell hamartoma”). The term
has also been applied to lesions or malformations composed of a variety of cardiac elements, and other tumours composed primarily of a single cell type (e.g.,
rhabdomyoma). The term hamartoma of
mature cardiac myocytes is used for a
distinct tumour in adults, composed of
cardiac myocytes. This lesion may be
single or multiple.
A
B
Fig. 4.07 Histiocytoid cardiomyopathy. A Electron microscopic illustration showing histiocytoid cells packed
with mitochondria. The diminished myofibrils are displaced to the periphery of the cell (arrows). B Higher
magnification showing abundant swollen mitochondria with disorganized cristae and dense membrane
bounded granules.
Etiology
The etiology of cardiac hamartoma is
unknown. Some have suggested that
these tumours may represent maturing
congenital rhabdomyomas. However,
there has been no association of hamartoma of mature cardiac myocytes with
other syndromes including the tuberous
sclerosis complex, making this unlikely.
Localization
Hamartomas of mature cardiac myocytes
may occur in the ventricles or atria, and
may be single or multiple {243}. Unusual
examples of diffuse multiple tumourlets
similar to so-called rhabdomyomatosis,
have also been described.
Clinical features
As is the case with most cardiac
tumours, the clinical features depend on
the location. Tumours in the atria may
result in supraventricular arrhythmias
and Wolf Parkinson White syndrome, and
those in the ventricles sudden death, or
no symptoms at all.
Macroscopy
They are usually poorly demarcated firm
white masses and range in size from 2
mm to 5 cm in greatest dimension. They
resemble normal myocardium, but the
bundles of muscle may appear disorganized and associated with bands of connective tissue.
Histopathology
They are composed of enlarged
myocytes with obvious cross striations,
and contain enlarged, irregular nuclei.
They are poorly demarcated and may
interdigitate with normal myocytes at the
edges of the tumour. The interstitium
258 Tumours of the heart - Benign tumours with myocyte differentiation
demonstrates
increased
collagen.
Interspersed fat cells may be present in
small numbers.
Immunoprofile
The tumours are similar to normal cardiac myocytes, and express actin and
myosin. Abnormal accumulations of
these intermediate filaments may be
appreciated, particularly of actin. There
is no evidence of proliferation by
immunohistochemical stains for Ki-67 or
PCNA.
Electron microscopy
The cells show features of myocytes, but
abnormal accumulations of actin and
myosin may be identified.
Differential diagnosis
The disorganized hypertrophied muscle
fibers of a hamartoma are also reminiscent of the disarray characteristic of
hypertrophic cardiomyopathy, but with
rare exception (apical variant), hypertrophic cardiomyopathy is not associated
with a focal mass lesion.
Prognosis and predictive factors
These tumours are benign neoplasms
and can be excised, resulting in cure.
However, arrhythmias and sudden death
may be the initial presentation.
B
A
Fig. 4.08 Hamartoma of mature cardiac myocytes. A The tumour was circumscribed, with the appearance
of muscle. B The tumour cells are hypertrophic, forming disorganized bundles with interstitial fibrosis.
Fig. 4.09 Adult cellular rhabdomyoma. Note the
monomorphic, bland spindled cells; their myogenic
nature is not clearly evident on routine stains.
Adult cellular rhabdomyoma
tumours, the absence of tumour necrosis, mitotic figures, myogenin expression,
and the presence of a well-defined
pseudocapsule help to distinguish it from
rhabdomyosarcoma.
Definition
Adult cellular rhabdomyoma is a benign
neoplasm of striated myocytes. A similar
tumour frequently occurs in the head and
neck region (extracardiac rhabdomyoma).
ICD-O code
8904/0
Epidemiology
The adult form of extracardiac rhabdomyoma occurs primarily in the head
and neck region of men and women over
40 years. Four cases of “extracardiac”
rhabdomyomas have been described in
the heart {241,2226}.
Clinical features and localization
Three of the four reported cases of adult
cellular rhabdomyoma have occurred in
the atria, and all have occurred in adults
from 35-55 years of age. Common to any
heart tumour, the mode of presentation is
often electrical disturbance such as
supraventricular tachycardia or nonsustained ventricular tachycardia. The
masses may be identified incidentally.
Macroscopy
They range in size from 2–5 cm. The
tumours are soft, bulging, tan to brown
and have a pseudocapsule. These fea-
tures distinguish these tumours from
other cardiac tumours with muscle differentiation.
Histopathology
These tumours are histologically distinct
from cardiac rhabdomyomas, and are
composed of tightly packed, round to
polygonal cells with eosinophilic, finely
granular cytoplasm, occasional vacuoles
and occasional spider cells. Conversely,
cardiac rhabdomyomas are composed
of large cells with clear cytoplasm containing abundant glycogen and many
spider cells.
Differential diagnosis
In contrast to congenital rhabdomyomas,
adult cellular rhabdomyomas occur in
adults, demonstrate evidence of cellular
proliferation e.g. by expression of Ki-67
antigen, and contain relatively few vacuolated or spider cells. Unlike hamartoma of mature cardiac myocytes, the
tumours are well circumscribed, and
although not as frequent as in congential
rhabdomyoma, some vacuolated cells
are usually present. Furthermore, the disorganized masses of myofilaments characteristic of hamartoma of mature cardiac myocytes are not seen. Rhabdomyosarcoma shares some features with
adult cellular rhabdomyoma. Despite the
evidence of cell proliferation in the latter
Histogenesis
The lesion is believed to be a true neoplasm of striated muscle origin.
Somatic genetics
Due to the rarity of these lesions, molecular and genetic characterization has not
been undertaken. In extracardiac rhabdomyoma, a reciprocal translocation
between chromosomes 15 and 17 and
abnormalities of the long arm of chromosome 10 have been described {680}.
Prognosis and predictive factors
The prognosis of adult cellular rhabdomyoma is unknown, but presumed to
be benign, based on the biologic behaviour of extracardiac rhabdomyomas in
adults. Late recurrences have been
described in extracardiac rhabdomyoma
{680}.
Adult cellular rhabdomyoma 259
Benign tumours of pluripotent
mesenchyme
A.P. Burke
H. Tazelaar
J.J. GomezRoman
R. Loire
P. Chopra
M. Tomsova
J.P. Veinot
T. Dijkhuizen
Cardiac myxoma
Embolism
Embolic phenomena are the second
most common manifestation (30-40% of
patients). Frequent sites of embolization
inclulde the central nervous system, kidney, spleen and extremities. Coronary
embolism may result in myocardial
infarction {524,1542}. There is some evidence that fibrous lesions are more likely
to produce valvular obstruction while
polypoid and myxoid ones are more likely to embolize {722,736}.
Definition
Myxoma is a neoplasm composed of
stellate to plump cytologically bland
mesenchymal cells set in a myxoid stroma.
ICD-O code
8840/0
Epidemiology
Cardiac myxoma represents one of the
most common benign cardiac tumours
{2013,2165}. In most surgical series, they
account for almost 80% of cases
{249,1986}. In large registries and repositories with significant referral bias myxomas represent between 20 and 40% of
primary cardiac tumours {249,1338}.
Patient age ranges from 2-97 years.
Mean age at presentation is 50 years
{1133}. About 90% of individuals are
between the ages of 30 and 60 years
{2165}. A recent analysis of 1,195 individuals with myxomas revealed that 67%
were female and 33% were male {2212}.
Patients with the myxoma (Carney) complex are generally younger and more
often male than patients with sporadic
myxomas.
A
Clinical features
Clinical presentation is diverse and
dependent upon tumour location and to
a lesser extent morphology {175,643,
1598,1616}. About 20% of cardiac myxomas are asymptomatic; they are usually
smaller than 40 mm {722,736}.
Cardiac symptoms
In over 50% of patients left atrial myxomas cause symptoms of mitral valve
stenosis or obstruction (dyspnoea and
orthopnoea from pulmonary oedema or
heart failure). Right atrial myxomas may
obstruct the tricuspid valve and cause
symptoms of right-sided heart failure.
The majority of patients have an abnormal physical examination, most characteristically a diastolic or systolic murmur.
A “tumour plop” may be occasionally
heard in early diastole {722,1598,1616}.
Abnormal, but nonspecific electrocardiographic changes may be identified in 2040% of patients and include atrial fibrilation or flutter and left and right bundle
branch block {643,1616}. Chest
roentgenograms also show only nonspecific findings, including cardiomegaly,
chamber enlargement, and pulmonary
oedema {1616}.
B
Fig. 4.10 Cardiac myxoma. A Long axis MRI view of the left ventricle demonstrating a well-circumscribed
myxoma (T) centered in the left atrium. The inferior portion of the mass abuts the tricuspid valve. B The
mass seen in the previous figure (T) originates from the atrial septum and is best demonstrated on the axial
view. The right-sided effusion and consolidation (E) are unrelated to the myxoma (the patient had metastatic malignant melanoma, with an incidental cardiac myxoma).
260 Tumours of the heart - Benign tumours of pluripotent mesenchyme
C.T. Basson
R. Rami-Porta
E. Maiers
A.E. Edwards
P. Walter
J.R. Galvin
S. Tsukamoto
D. Grandmougin
P.A. Araoz
Systemic symptoms
These are possibly related to IL-6 production by tumour cells. They are seen in
approximately 20% of patients and
include myalgia, muscle weakness,
arthralgia, fever, fatigue and weight loss.
Although infection of a myxoma is rare,
when present the initial manifestations
mimic those of infective endocarditis,
and can include fever, chills, petechiae,
subconjunctival haemorrhages, Osler
nodes and positive blood culture.
Anaemia, leukocytosis and elevated erythrocyte sedimentation rate are the most
common laboratory findings {175,1616}.
Most myxomas are sporadic, although
syndromic and familial cases (Carney or
myxoma complex) are well recognised.
In familial cases, the patients present at
a younger age, they occur in unusual
locations and have a higher recurrence
rate than in non-familial cases
{296,2114}.
Imaging
At echocardiography carciac myxomas
typically appear as a mobile mass
attached to the endocardial surface by a
stalk, usually arising from the fossa
ovalis. Myxomas with this appearance
can be confidently diaganosed by
echocardiography and further imaging is
not necessary {1298}. In fact, because
the tumours are usually small and
mobile, myxomas are typically better
defined by echocardiography than by
either MRI or CT, because echocardiog-
A
B
C
D
E
F
Fig. 4.11 Cardiac myxoma. A This incidental finding at autopsy is a sessile smooth surfaced mass attached
to the endocardium of the let atrium at the level of the oval fossa. Note the relationship to the mitral valve,
which may often become partly obstructed in patients with left atrial myxoma, resulting in pulmonary hypertension. B Myxoma of the left atrium, with typical localization at the fossa ovalis. C Cut surface of a papillary myxoma of the left atrium. D Papillary myxoma with necrosis, left atrium. E Left atrial myxoma after
resection. F Left atrial myxoma with an old and recent haemorrhages.
raphy has the best spatial and temporal
resolution. If the narrow stalk is not visible, the diagnosis cannot be made by
echocardiography and further imaging,
usually MRI, is necessary to show the
tumour’s margins and to exclude tumour
infiltration. At MRI and CT myxoma
appears as an intracavitary heterogeneous, lobular mass. As with echocardiography, if the narrow stalk is visible, myxoma can be diagnosed by MRI or CT
{66}.
Macroscopy
Cardiac myxomas are intracavitary
masses that occur most often in the left
atrium {361}. They arise from the endocardium of the atrial septum near the
fossa ovalis in 85-90% of cases. Most of
the remainder are located in the right atrium. Rarely, they arise in the ventricles.
Multiple tumours occurring at sites other
than fossa ovalis and ventricles are generally found in the inherited form of cardiac myxoma. Very rarely, cardiac myxomas have also been documented to
occur on valves and chordae tendineae.
The external appearance, consistency,
size and weight are extremely variable.
They may be as small as a few millimeters and as large as 14 cm in diameter.
The weight ranges from 2-250 gm. Tiny
cardiac myxomas may be totally asymptomatic and discovered incidentally at
surgery for another purpose or autopsy.
Larger ones are either sessile or pedunculated, but the site of attachment is
always discrete and usually in the region
of the fossa ovalis. Occasionally, the
stalk may be long, resulting in free mobility of the tumour within the atrial cavity.
Myxomas are ovoid, globular, lobulated
or polypoid. They may be smooth and
glistening or have multiple papillary, villous, finger-like projections. They may be
grey white and fibrous, gelatinous and
myxoid, or a combination of both. The
papillary structures may be quite friable
increasing the risk of embolisation.
Superficial thrombi also embolize.
Marked variation in colour is characteristic. Pale grey, pearly white or yellow
brown areas are frequently admixed with
haemorrhagic dark brown or red areas.
Tumour consistency depends on the
quantity and distribution of fibrous tissue,
and calcification. Rarely, the bulk of the
tumour becomes calcified {120,1180}.
Histopathology
The myxoma cells may be arranged
singly, in cords, or in vasoformative ring
structures {245,361,1625}. The cells can
be elongated, fusiform or stellate. They
contain modest amounts of eosinophilic
cytoplasm. Nuclei are oval, round, or
elongated and mitoses are very rare.
Myxoma cells have a tendency to form
primitive or differentiated vessels, reflected in expression of endothelial markers.
Less myxoid stroma often forms a halo
around the vascular formations.
The stroma contains variable amounts of
proteoglycans, collagen and elastin. It
shows strong reactivity with alcian blue,
resistant to predigestion by hyaluronidase. The vessels within the tumour are
thin-walled and lack pericytes. Occasionally, cavernous vascular spaces containing blood or proteinaceous material
are encountered. Thick walled blood vessels with prominent muscular walls are
present predominantly at the base of
tumour and in the stalk. Extravasated red
cells, foci of recent and organizing
haemorrhage and hemosiderin deposition are frequent. Hemosiderin is seen
free within the stroma, within histiocytes
and myxoma cells. Variable numbers of
lymphocytes, plasma cells, macrophages, dendritic cells, and mast cells
may be present.
Gamna-Gandy bodies as seen in chronic venous congestion of the spleen may
be encountered infrequently. Calcification and metaplastic bone formation
may also occur. The latter are more frequent in right atrial myxomas. The surface is usually composed of a single
layer of flattened cells, but multilayering
and tufting may occur.
Cardiac myxoma 261
Heterologous components
Well-defined columnar epithelium, occasionally forming glands occurs in about
2% of myxomas. The epithelium may
show moderate cytologic atypia, mitotic
activity and express cytokeratin. Age
and sex distribution of patients, signs
and symptoms, frequency of syndromic
association and sites of occurrence are
similar for cardiac myxoma with or without glands. Recognition of the glands as
a component of a myxoma is important
since these structures may be confused
with metastatic adenocarcinoma. The
glandular cells are positive for PAS-diastase, alcian blue and mucicarmine; they
stain for cytokeratin (diffuse cytoplasmic
staining with antibodies to cytokeratin 7,
AE1/AE3, 4betaE12 and Cam 5.2; and
focal staining for cytokeratin 20), EMA
(diffuse cytoplasmic), and CEA (apical
cell border). Reactivity for CA19.9 has
also been observed on the apical epithelial membrane of the glandular component of a myxoma from a patient with elevated serum CA19 {1190}. Foci of
extramedullary haematopoiesis may be
seen in 7% of myxomas {245}. Thymic
rests have also been observed {245}.
Immunoprofile
The cells are cytokeratin negative, variably S-100 positive, and variably positive
for smooth muscle and endothelial markers e.g. CD 34 and CD31 {362,1269,
1625,2013}. Calretinin is expressed in
about 75% of cardiac myxomas {16}.
Histogenesis
Some years ago myxomas were considered nothing more than organised thrombi. Their neoplastic nature is supported
by the presence of chromosomal abnormalities {489}, abnormal DNA content
{1226} and the presence of microsatellite
instability {1853}. The presence of heterologous elements, however, still suggest to some that they may be reactive or
hamartomatous {1925}. The origin of
myxoma cells is unclear. They are
thought to arise from subendothelial
vasoformative reserve cells or primitive
cells which reside in the fossa ovalis and
surrounding endocardium. The minute
endocardial structures described by
Prichard {1618} do not seem to correspond to the hypothetical subendothelial
pluripotential vasoformative reserve cells
from which the myxomas would arise,
because they do not share the immuno-
A
B
C
D
E
F
Fig. 4.12 Cardiac myxoma. A Numerous rudimentary vessels. B Three stages of rudimentary vessels.
C A primitive endothelial marker, CD34 is often present within the central areas of the vascular structures
formed by cardiac myxoma. D Cardiac myxoma glands with PAS-positive-diastase resistant material consistent with mucus. E Cardiac myxoma with complex glands whose cells show moderate cytologic atypia.
F Cytokeratin 7 staining of a cardiac myxoma with heterologous components.
histochemical properties of myxoma
cells {15,16}. On the other hand, cardiomyocyte-specific transcription factor
mRNAs have been recently found in RNA
extracted from myxoma lysates, suggesting cardiomyogenic differentiation in
myxoma cells and a possible origin in
cardiomyocite progenitor cells {1037}.
Genetic susceptibility
Although most myxomas are sporadic,
some have been associated with the
myxoma complex {295,483}. This autosomal dominat syndrome has been
reported under the acronyms NAME
(nevi, atrial myxoma, myxoid neurofibroma, ephelides), LAMB (lentigines, atrial
myxoma, mucocutaneous myxomas,
blue nevi), and more recently as Carney
syndrome {295,299,530}. This syndrome
includes cardiac myxomas and extracar-
262 Tumours of the heart - Benign tumours of pluripotent mesenchyme
diac manifestations: abnormal skin pigmentation (lentigines and blue nevi), calcifying Sertoli-Leydig testicular tumours,
cutaneous myxomas, myxoid breast
fibroadenomas, pigmented adrenal cortical hyperplasia, pituitary hyperactivity,
psammomatous melanotic schwannoma
and thyroid tumours {295}. Familial myxomas are estimated to account for 7% of
atrial myxomas {299}, are more often
multiple, recurrent and right sided, as
compared to sporadic myxomas. The
affected patients are also younger, most
presenting at 20-30 years of age
{530,1133,1544}.
Somatic genetics
The chromosomal patterns of sporadic
cardiac myxoma are characterised by
extensive intratumour heterogeneity. In
the seventeen cases published to date,
multiple unspecific chromosome aberrations have been reported, including
dicentric chromosomes and, in particular, telomeric associations {489,497,498,
502}. Intratumour heterogeneity, as found
in a variety of tumour types and grades
{688}, is considered a sign of genetic
instability presumably resulting from disruption of genes that control genomic
integrity. Studies of cardiac myxomas
suggest that the chromosomal regions
12p1 and 17p1 may play a specific role
in the development of these neoplasms
since they are frequently rearranged
{497}.
Cytogenetic analyses of three cases of
cardiac myxoma derived from patients
with the myxoma syndrome reveal chromosome patterns similar to those
observed in sporadic cases {489,1658,
1882}. Whether there is a common
genetic mechanism underlying sporadic
and familial cardiac myxomas is unclear.
Based on linkage analysis, 2 loci have
been proposed for genes causally related to the myxoma syndrome: 2p16
{1882} and 17q2 {299}. Recently, a gene
located at 17q24 was cloned that
showed mutations in myxoma patients
{122,598,1018}. This gene, PRKAR1A,
represents a putative tumour suppressor
gene, coding for the type 1 alpha regulatory subunit of protein kinase A (CNC1,
OMIM #160980). No causal gene has
been identified at the 2p16 locus, and
some families that were initially thought
to have disease related to this locus
actually have chromosome 17q24
PRKAR1A mutations {122}. At least one
further locus remains to be identified. As
yet, neither mutations of PRKAR1A nor
loss of heterozygosity of markers at 17q2
and 2p16 have been found in sporadic
cardiac myxomas {598}.
Flow cytometry shows abnormally high
tetraploid DNA patterns in all cases of
syndromic myxomas, whereas in sporadic myxomas it is present only in about
20%.
Prognosis and predictive factors
There is a remarkably different prognosis
between patients with sporadic and
familial myxomas. Patients with sporadic
tumours have a good prognosis, with 13% recurrence rate {1275,296,2227}.
However, about 10% of patients with
familial myxomas either have recurrent
tumours or develop another tumour in a
different location {1276,1598}. The recur-
A
B
Fig. 4.13 Papillary fibroelastoma. A Papillary fibroelastoma from aortic valve. Note multiple translucent papillary fronds. B Multiple papillary fibroelastomas (greater than 40) developing 17 years following open heart
surgery. From A.N. Kurup et al. {1105}.
rence interval in one series was 47.8
months {296}. The probability of recurrence has been related to DNA chromosomal pattern {296,1276}. Patients with a
familial tumour need to followed long
term.
Embolization is the major complication of
myxoma and may result in ischemic
symptoms in a variety of arterial beds.
Intracranial aneurysm due to embolization is also a rare, but potentially morbid,
complication. The etiology of these
aneurysms is unclear but histologic verification of myxoma cells in arterial walls
has been reported {1758}.
Treatment
Immediate surgical resection is advised
when the diagnosis of cardiac myxoma is
suspected {1454}, because of the risk of
embolism {2001}. The tumour is removed
under cardiac arrest with cardiopulmonary bypass. Minimal manipulation
and gentle management of the heart is
recommended so as not to precipitate
embolism. After the tumour is resected,
the cardiac chamber should be irrigated
with saline solution to wash out residual
tumour fragments.
The approach to a left atrial myxoma is
usually through a vertical incision. When
the tumour is not large, a transseptal
approach useful, whereas a transseptal
biatriotomy {516} is recommended for a
large tumour. As the majority of left atrial
myxomas arise from the interatrial septum, the tumours can be removed en
bloc with a 5 mm margin of normal tissue. The fossa ovalis, where the pretumour cells of myxomas are thought
likely to exist {2102}, should also be
excised if possible. For a right atrial myxoma, direct caval cannulation avoids
tumour fragmentation. When direct cannulation to the inferior vena cava is
impractical, a cannula should be inserted from the femoral vein for the inferior
vena cava. Tumour resection with the full
thickness of the septum and patch repair
is required for tumours with a broad
based attachment. However, when the
tumour originates from the atrial wall,
resection of the attachment, and 5 mm of
normal tissue including endocardium
and underlying myocardium are recommended.
Papillary fibroelastoma
Definition
An endocardial based papilloma lined by
endothelial cells with proteoglycan rich
avascualar stroma, usually rich in elastin.
Synonyms
Giant Lambl excrescence, fibroelastic
papilloma
Epidemiology
Papillary fibroelastoma is a rare and
benign tumour representing less than
10% of primary cardiac tumours
{121,247}. The true incidence is difficult
to determine, as the tumour may be overlooked and there is morphologic overlap
with Lambl excresences, a reactive agerelated valvular lesion {249,2080} In
recent series of surgically excised cardiac tumours papillary fibroelastoma represents the second most frequent benign
lesion.
Papillary fibroelastoma is the most common primary tumour of cardiac valves. In
two recent series of primary valve
tumours, papillary fibroelastoma constituted 73% and 89% of cases {531,1714}.
Mean age of the patients is 60 years
(range, newborn to 83 years) and there is
an equal gender predilection {1714,
1903}.
Papillary fibroelastoma 263
Etiology
The histogenesis continues to be a
source of controversy. Various gross,
microscopic, and molecular characteristics of papillary fibroelastoma have led to
the lesions’ being described as neoplasms, hamartomas, organized thrombi,
and unusual endocardial responses to
trauma. The histochemical presence of
fibrin, hyaluronic acid, and laminated
elastic fibers within the fronds supports
the hypothesis that papillary fibroelastomas may be related to organizing
thrombi. Evidence favouring the hamartoma hypothesis includes a histologic
appearance that suggests the proliferation of miniature tendinous cords and
apparent congenital papillary fibroelastomas associated with other congenital
cardiac anomalies. Due to the presence
of dendritic cells and cytomegalovirus in
the intermediate layers of some papillary
fibroelastomas, a recent study proposed
that papillary fibroelastomas may be
related to a chronic form of viral endocarditis {734}.
Repetitive hemodynamic trauma may
contribute to their development as they
have been reported in association with
diseases resulting in abnormal flow of
blood in the heart including rheumatic
heart disease, hypertrophic cardiomyopathy, mitral valve prolapse and atrial
septal defect, among other diseases.
However, the mechanisms by which such
hemodynamic abnormalities contribute to
papillary fibroelastoma growth are unclear.
There is increasing evidence that at least
a subset (18%) of these tumours develop
as a result of iatrogenic factors, including
thoracic irradiation and open-heart surgery (subaortic septal myectomy, valve
repair, valve replacement and repair of
congenital defects {1105}. In contrast to
sporadic cases, which are most common
on cardiac valves, iatrogenic papillary
fibroelastomas tend to occur in a variety
of non-valvular endocardial surfaces,
usually in close proximity to the predisposing iatrogenic factor, e.g. in the
chamber most closely associated with
the site of surgery.
Localization
Ninety percent of papillary fibroelastomas occur on heart valves, including
aortic, posterior and anterior mitral
leaflets {531,597,842,1397,1819,2015},
mitral chordae and papillary muscles
{313,659}. Unusual locations include the
Table 4.02
Immunohistochemical profile of cardiac papillary fibroelastomas.
From D. Grandmougin et al. {734}
Marker
Central fibrous
core
Intermediate layer
Endothelial border
Vimentin
(+)
(+)
(+)
S 100 Protein
(-)
(+)
(-)
CD 31
(-)
(-)
(+)
CD 34
(-)
(-)
(+)
Factor VIII
(-)
(-)
(+)*
CMV-LMP-1
(+)
EBV-LMP-1
(-)
*Staining intensity decreased in comparison to the adjacent normal endocardial endothelium with an
immunoreactivity ratio of 0.4
tricuspid and pulmonary valves, right
and left atrial and ventricular endocardial
walls, Chiari’s network, and coronary
ostia {43,202,254,913,977,1179,1770,
2249}. Autopsy series show an equal
right and left heart distribution {205,
531,1274}. However, surgical series have
a high prevalence (81%) of left sided
papillary fibroelastomas because leftsided lesions are much more frequently
symptomatic.
Tumours are found most commonly
(69.5%) on diseased valves - 37.8%
post-rheumatic valves and 62.2% valves
with fibrosis and calcification {1903}.
Papillary fibroelastomas have been
likened to Lambl excrescence, but unlike
Lambl excrescences, which occur at the
line of closure of semilunar valves, papillary fibroelastomas occur anywhere on
the valve surface.
Clinical features
The clinical diagnosis of papillary fibroelastoma can be difficult because
embolic complications can mimic a variety of underlying diseases {1714}.
Integrity of the superficial endothelial
layer of the fronds has been demonstrated to be the main element leading to
occurrence of embolic events {734}.
Embolism is related to the aggregation of
platelets and fibrin {567,734,742}.
Lesions adjacent to coronary ostia may
prolapse resulting in angina, syncope or
sudden death {205,262}. The majority of
264 Tumours of the heart - Benign tumours of pluripotent mesenchyme
surgically excised cases occur in
patients with symptoms related to cerebral ischemia. The diagnosis is made by
multiplanar transthoracic and transesophageal echocardiography {713,
1151,1770,2015}. High-resolution echocardiography shows an echolucent centre.
Macroscopy
Papillary fibroelastomas range in size
from 2-50 mm in greatest dimension,
although the majority are less than 10
mm. They are generally opalescent
white, but this colour may be obscured
by thrombus. They are usually attached
to the endocardial surface by a short single stalk, but those with more than one
attachment to the endocardium have
been observed. Papillary fibroelastomas
have multiple papillary fronds and, particularly when immersed in water, they
resemble a pom-pom or sea anemone.
Papillary fibroelastomas most often
occur singly (80-90%), but among
patients with iatrogenic tumours, multiple
tumours (2 to greater than 40) occur with
great frequency (67%). Such tumours are
less likely to occur on the valves and
have been reported in a wide variety of
locations (on papillary muscles, tendinous cords, and atrial and ventricular
septal and free walls).
Histopathology
Papillary fibroelastomas have a superficial endothelial layer, an intermediate
A
B
C
D
Fig. 4.14 Papillary fibroelastoma. A Location at the aortic valve. B Movat pentachrome stain demonstrating an incidental papillary fibroelastoma on the surface of
the valve. In this example, there is little elastic tissue within the papillae. C Papillary fibroelastoma showing multiple fronds with prominent elastic tissue cores
(elastic van Gieson). D Fibroelastic papilloma with young vegetations.
layer rich in proteoglycans and a central
avascular core. The inner layers contain
fibroblasts and occasional inflammatory
cells including macrophages and dendritic cells {742,1703}. Elastic fibres are
most prominent in the core but may be
sparse or absent in the distal parts of the
papillae. Acute and organizing thrombi
may be seen on the surface and obscure
the papillary surfaces.
Immunohistochemistry
Immunohistologic studies demonstrate a
disparity between surface and deeper
layers. Surface endothelial cells express
vimentin and CD34 with some loss of
intensity for CD31 and factor VIII related
antigen in comparison to normal endocardial endothelium. It has been proposed that the decreased expression of
endothelial markers indicates endothelial
trauma or dysfunction {734,1200,1703}.
Spindle cells in deeper layers may focally express S100 protein. The S100 cells
likely represent competent antigen presenting dendritic cells. The presence of T
cells has not been investigated in these
regions.
Papillary fibroelastoma 265
Haemangioma
Definition
Haemangiomas (angiomas) are benign
tumours composed predominantly of
blood vessels. The histologic classification includes those composed of multiple
dilated thin-walled vessels (cavernous
type), smaller vessels resembling capillaries (capillary type), and dysplastic malformed arteries and veins (arterio-venous
haemangioma, cirsoid aneurysm). Cardiac haemangiomas often have combined features of cavernous, capillary and
arteriovenous haemangiomas, and many
contain fibrous tissue and fat. These features are reminiscent of intramuscular
haemangiomas of skeletal muscle.
ICD-O code
9120/0
Clinical features
Most cardiac haemangiomas are discovered incidentally but patients may present with dyspnoea on exertion, arrhythmias, right-sided heart failure, pericarditis, pericardial effusion, and failure to
thrive. Patients may have associated
vascular syndomes e.g. KasabachMerritt {675}.
Imaging
At echocardiography, haemangiomas
are usually hyperechoic, circumscribed,
and intracavitary solitary masss. At MRI,
hemaniogmas may be intermediate to
high on T1 weighted images, often are
very intense on T2 weighted images, and
A
H. Tazelaar
A.P. Burke
G. Watanabe
C.T. Basson
also enhance brightly with contrast
administration {1003}. At CT the tumors
are usually circumscribed, low attenuation, heterogeneous and also enhance
brightly with contrast administration.
{737}. The circumscribed, non-infiltrative
appearance of haemangioma, particularly on MRI which is most sensitive to tissue infiltration, can be used to suggest
that the neoplasm is benign, but a specific diagnosis cannot be made with
imaging.
Localization
The most frequent locations are the lateral wall of the left ventricle (21%), the
anterior wall of the right ventricle (21%),
the interventricular septum (17%) and
occasionally, the right ventricular outflow
tract {226}.
Macroscopy
The tumours are often large and gross
appearance depends on the size of the
vascular spaces in the tumour. The capillary type is frequently slightly raised
from the endocardial sruface and
appears red to purple. Intramuscular
types will appear infiltrative. Cavernous
haemangiomas are usually large and are
also poorly circumscribed.
Histopathology
Capillary haemangiomas are composed
of nodules of small capillary-size vessels,
each of which is subserved by a “feeder”
B
Fig. 4.15 Cardiac haemangioma. A MRI of right atrial haemangioma in a newborn who underwent partial
surgical resection of the tumor. ECG-triggered breath-hold T2-weighted fast spin echo sequence shows a
markedly hyperintense signal from the tumor (arrow). B Echocardiographic imaging of cardiac haemangioma involving the interventricular septum in a 7-year-old boy.
266 Tumours of the heart
vessel. This lobular or grouped arrangement of vessels is helpful for distinguishing these benign from malignant vascular proliferations. Mast cells and factor
XIII-positive interstitial cells are a consistent feature.
Intramuscular cardiac haemangioma has
superficial resemblance to arteriovenous
malformation, with the presence of heterogeneous vessel types, including muscularized arteries, veins, and capillaries.
In contrast to capillary haemangioma,
they are infiltrative lesions and occur
within the myocardium. They are histologically identical to intramuscular haemangiomas within skeletal muscle, and
may possess, in addition to the vessels,
fat and fibrous tissue. Because of the latter features, some intramuscular cardiac
haemangiomas are misclassified as lipomas or fibrolipomas.
Cavernous haemangiomas are composed of large dilated vascular spaces.
They tend to infiltrate the myocardium.
The lining cells are bland and flattened
and mitotically inactive.
Genetic susceptibility
Genetic susceptibility to cardiac haemangiomas has not been identified.
Extracardiac haemangiomas occur in a
variety of contexts. They may be single
sporadic lesions or multiple lesions that
are components of complex genetic syndromes. Capillary haemangiomas occur
in up to 10% of live births and are the
most frequent tumour in newborns
{1409}. When these tumours occur in the
absence of associated syndromes, they
may represent manifestations of an autosomal dominant mendelian trait (OMIM
#602089) {7}. Linkage analyses {224,
2101} of multiplex kindreds affected by
hereditary capillary haemangiomas have
identified loci on chromosome 5 (q31q33 and q13-q22) that appear to contain
as yet unidentified causal disease
genes.
A wide array of complex syndromes,
such as von Hippel Lindau syndrome
(OMIM #193300) and SC phocomelia/
Roberts syndrome (OMIM #269000), that
can be transmitted in a mendelian fashion include haemangiomas as components of their clinical presentations. The
Klippel-Trenaunay-Weber syndrome, in
which cutaneous haemangiomas occur
in the setting of osseous hypertrophy,
shows familial clustering, but a clear
mode of inheritance has not been established. Autosomal paradominant and
dominant modes of inheritance have
been proposed {306,775}. Translocations {2105 2130} have been identified
in 2 Klippel-Trenaunay-Weber patients,
t(5;11) (q13.3;p15.1) and t(8;14)(q22.3;
q13), but specific gene defects remain to
be identified.
Somatic genetics
Specific genes have been associated
with two disorders involving arteriovenous malformations. Mutations in the
gene on chromosome 9p21 encoding the
endothelial cell-specific receptor tyrosine
kinase TIE2 cause the autosomal dominant Bean or “Blue rubber-bleb nevus”
syndrome (OMIM #112200) and familial
multiple cutaneous and mucosal venous
malformations (OMIM#600195) {2084}. At
least some cases of hereditary cerebral
cavernous
malformations
(OMIM
#116860) are caused by mutations in the
chromosome 7q21-q22 Krev interaction
trapped-1, KRIT-1, gene {1110}. KRIT1
normal binds to RAP1A, a Ras GTPase,
and the disease causing mutations
appear to disrupt these interactions.
Other genetic loci for this disorder have
been identified at chromosomes 17p15p13 and 3q25.2-q27 and remain to be
studied. The genetic and clinical relationship of this disorder to hereditary neurocutaneous angioma (OMIM #106070) is
unclear.
Syndromic associations
The majority of cardiac haemangiomas
are sporadic, without evidence of extracardiac vascular lesions. Rarely, there
may be extracardiac haemangiomas of
the gastrointestinal tract and port-wine
stain of the face. Giant cardiac haemangiomas can result in thrombosis and
coagulopathies (Kasabach-Merritt syndrome) {239,675}.
Fig. 4.16 Haemangioma. This lesion has some features of arteriovenous malformation, with a non-uniform
collection of thick walled arteries, dilated veins and capillaries. In addition, there is fat and fibrous tissue,
as ooccasionally seen in an intramuscular haemangioma.
Fig. 4.17 Haemangioma. This tumor shows a relatively uniform population of capillary type vessels with variable degrees of dilatation. The myxoid background may suggest myxoma, but other features of myxoma are
absent, and the vessels are mature.
Haemangioma 267
Benign tumours with myofibroblastic
differentiation
Cardiac fibroma
8810/0
Synonyms
Fibroelastic hamartoma, fibrous hamartoma.
Epidemiology
Most cardiac fibromas are discovered in
children and often before one year of age
{737,1944}. Prenatal diagnosis with
sonography is possible {121,134,538}.
However, cases are also reported in
adults {307} and even as an incidental
finding in the elderly {2093}. There is no
sex predominance. The incidence is very
low with only about 200 cases reported
to date.
Localization
The most common site of cardiac fibroma is the ventricular septum, but the free
walls of the left and right ventricle are
A
V. T. de Montpréville
C.T. Basson
G. Watanabe
P.A. Araoz
other common locations. Atrial fibromas
are quite rare.
Definition
Fibroma is a rare primary heart tumour
composed of fibroblasts or myofibroblasts with a matrix containing collagen. It
almost exclusively occurs within the
myocardium of the ventricles or ventricular septum. It is not clear whether it is a
hamartoma or a true neoplasm. Because
most cases occur in infants and children
it is likely congenital.
ICD-O code
E. Dulmet
A.P. Burke
T. Geva
H. Kamiya
H. Tazelaar
Clinical features
One-third of cardiac fibromas cause
symptoms because of their mass effect,
either through obstruction of blood flow
or interference with valvular function and
patients present with cardiac failure or
cyanosis. In another third of the cases,
cardiac fibromas, whatever their location,
cause significant arrhythmias, syncope
or sudden death. The remaining patients
are asymptomatic and tumours are discovered because of heart murmur or a
radiographic abnormality. Embolic phenomena are not a feature of cardiac fibromas {121,134,538,737,1944}.
Imaging
At echocardiography fibromas typically
appear as a large, well-circumscribed,
solitary mass in the septum or ventricular
free wall {1010,1242} and in some cases
may be confused with hypertrophic cardiomyopathy {66}. The tumors are frequently very large and may cause
obstruction, which can be assessed by
colour Doppler. MRI likewise shows a
large, solitary, homogeneous myocardial
mass centered in the ventricles {1003,
1215,1660}. Because of the fibrous
nature of the tumour, the signal intensity
is often less than that of adjacent uninvolved myocardium, and contrast-
B
A
B
Fig. 4.19 Cardiac fibroma. A The tumour fills the left
ventricular cavity, which is obliterated. The right
ventricle and tricuspid valve are on the left.
B Cardiac fibroma with prominent whorled surface.
enhanced imaging usually demonstrates
a hypoperfused tumour core. CT also
shows a large, solitary, ventricular mass,
which is usually low attenuation on CT.
Unlike other imaging modalities CT may
detect calcification which is a helpful feature in making a confident diagnosis.
{66}. Overall, the imaging finding of a
C
Fig. 4.18 Cardiac fibroma. A Left ventricular fibroma in a 6-month-old infant. A. ECG-triggered breath-hold proton-density fast spin echo MRI with double inversion
recovery sequence in the axial plane showing a large inhomogeneous mass involving the left ventricular free wall. B MRI of left ventricular fibroma in a 6-monthsold infant. Post-gadolinium imaging shows enhancement of the uninvolved myocardium and the tumour’s periphery. Note the hypoperfused tumor core.
C Echocardiogram of an infant with a large right ventricular fibroma causing right ventricular outflow tract obstruction.
268 Tumours of the heart - Benign tumours with myofibroblastic differentiation
ages, but is somewhat more common in
older individuals. Wavy elastic fibers are
frequent and may be prominent. Focal
myxoid change in the stroma and chronic inflammation may also be present
{244}.
Immunoprofile
Tumour cells express vimentin and
smooth muscle actin, both in cellular and
fibrous lesions. They do not express
desmin, CD34 or S-100 protein.
Reacitivity for markers of proliferation,
are much more frequent in cellular
tumours than in the fibrous ones {451}.
Somatic genetics
A clonal translocation has been
described in cell cultures of a subepicardial fibroma resected from an infant.
Cytogenetic analysis in this tumor
showed a clonal reciprocal translocation,
46,XY,t(1;9)(q32;q22),inv(9)(p11q12)c
{572}.
A
B
Fig. 4.20 Cardiac fibroma. A Fibroma infiltration into adjacent myocardium. B Calcifications in a fibrous
lesion from a 19-year-old patient.
solitary, very large, hypovascular mass in a
child is suggestive of a cardiac fibroma.
Macroscopy
They are typically rounded masses that
are fibrous, white and whorled, reminiscent of uterine leimyomas. The margin
may be either circumscribed or infiltrative. In some cases, fibromas are massive and can obliterate ventricular cavities. They are nearly always mural,
although polypoid endocardial based
lesions have been reported. Most occur
singly. The mean diameter is 5 cm.
Histopathology
Fibromas are composed of bland-looking
spindle cells forming loose intersecting
bundles. They are not encapsulated and
extend into the surrounding myocardium.
Even in grossly circumscribed cases,
entrapped myocytes can often be seen
deep within the tumours, far from the
gross margins {244,451}. The fibroma
cells have oval or tapered nuclei without
nucleoli. Their cytoplasm is pale. These
cells are associated with abundant collagenous stroma, which increases with
the age of the patient. Cellular lesions are
observed in infants during their first
months of life, while fibromas in older
patients contain large amounts of collagen. Mitoses and foci of extramedullary
haematopoiesis may be present in cellular tumours {451}. Calcification is
observed in lesions from patients of all
Genetic susceptibility
Approximately 3% of patients with Gorlin
syndrome have cardiac fibromas {418,
547,716}. Gorlin syndrome (or nevoid
basal cell carcinoma syndrome) is an
autosomal dominant disorder characterized by generalized body overgrowth,
jaw keratocysts, developmental abnormalities of the skeleton, and a predisposition to neoplasms, specifically cardiac
fibroma. Gorlin syndrome results from
germline mutations in the PTC gene,
which maps to chromosome 9q22.3 and
is homologous to the Drosophila patched
(ptc) gene {756}. The ptc gene encodes
a transmembrane protein in Drosophila
that represses the Hedgehog signaling
pathway to control cell fate, growth, and
development {756,893}. These data suggest that the PTC gene not only functions
as a tumour suppressor gene, but also
plays a critical role in development.
However, the precise role of the PTC
gene in myocardial cell growth and differentiation and its role in the development of cardiac fibroma remains to be
defined {2077}.
Associated hydrocephalus, cleft lip and
palate, and Sotos syndrome (megalencephaly with gigantism) have been
reported {446,1242}.
Prognosis and predictive factors
The cardiac fibroma is benign, but its
nature of slow but continuous growth
Cardiac fibroma 269
may cause conduction defects and
arrhythmias. Extension into the ventricular free walls may result in atrioventricular
valve inflow or arterial outflow obstruction. Spontaneous regression as can
occur with congenital rhabdomyoma has
not been observed.
Treatment
Operative intervention is usually required
{451,615,2071}. When the tumour proves
unresectable, heart transplantation is an
option {731,2071}. However, favourable
late results even after incomplete excision have been reported {132,307,1880}.
Inflammatory myofibroblastic
tumour
Definition
Inflammatory myofibroblastic tumour is
composed of myofibroblasts accompanied by a variable number of inflammatory cells including lymphocytes, macrophages, plasma cells and eosinophils.
ICD-O code
8825/1
Synonyms
Plasma cell granuloma, inflammatory
pseudotumour and possibly inflammatory fibrosarcoma
Epidemiology
These tumours are very rare in the heart,
and only small series and case reports
appear in the literature.
Localization
Although there is a predilection for the
ventricles, especially the right ventricular
outflow tract, any site in the heart may be
involved {1177}.
Clinical features
Signs and symptoms
There are no specific signs or symptoms
related to cardiac inflammatory myofibroblastic tumour, as these are related to
location within the heart. One cardiac
Fig. 4.21 Inflammatory myofibroblastic tumour of the left ventricle. Plump spindle cells are arranged in a
haphazard fashion and focally surround myocytes. A modest chronic inflammatory cell infiltrate including
plasma cells is also present.
inflammatory myofibroblastic tumour has
been reported in a patient with systemic
vasculitis and another tumour regressed
spontaneously.
Macroscopy
Inflammatory myofibroblastic tumours of
the heart are large lesions, measuring up
to 8 cm {451}. Grossly, they tend to have
relatively narrow attachments to the
endocardium and project into the ventricular lumen.
Histopathology
Inflammatory myofibroblastic tumor is
composed of spindled myofibroblasts,
fibroblasts, chronic inflammatory cells
and sometimes eosinophils. Various
combinations of these cell types make
these tumours quite variable from one
case to another Occasional mitoses and
foci of necrosis may be present.
Immunoprofile
The tumour cells strongly express actin
and vimentin, but not desmin, CD34, S-
270 Tumours of the heart - Benign tumours with myofibroblastic differentiation
100 protein and p53. It is unknown if
ALK-1 expression is diagnostically useful
in cardiac inflammatory myofibroblastic
tumours as is the case with extracardiac
tumours.
Differential diagnosis
In contrast to fibromas, inflammatory
myofibroblastic tumours are endocardial
lesions, and there is often organizing fibrin thrombus on the surface. In addition
the tumours are more histologically variable, the spindle cells are larger than in
fibromas and the cells often have nucleoli.
Prognosis and predictive factors
The biologic behavior of inflammatory
myofibroblastic tumour is that of a lowgrade lesion with the propensity for recurrence, but overt malignancy is rare. No
case of metastases arising from cardiac
inflammatory myofibroblastic tumour has
been reported.
Cardiac lipoma
A.P. Burke
P.A. Araoz
Definition
Benign tumour composed of mature,
white adipocytes.
ICD-O code
8850/0
Epidemiology
Cardiac lipoma is rare and found in fewer
than 1 in 10,000 autopsies {1116}.
Lipomas generally account for only 0.53% of excised heart tumours {121,573,
952,1257,1672}. Higher estimates of up
to 10% of heart tumours are likely because lipomatous hypertrophy, a separate entity, has been included
{1257,1628}. Lipomas occur in children,
but account for less than 2% of heart
tumours similar to the relative incidence
in adults {134}.
Localization
Cardiac lipomas may occur anywhere in
the heart. There is a predilection for the
pericardium and epicardial surfaces
{540,1125,1628,2060}, where they may
attain enormous sizes. Other sites
include the ventricular septum {1869},
and cardiac valves. When they involve
Fig. 4.22 Lipomatous hypertophy of atrial septum.
Fig. 4.23 Lipomatous hypertrophy. Lipomatous hypertrophy of atrial septum. Note the multivacuolated
adipocytes which can mimic liposarcoma.
the latter site, the designation “fibrolipoma” has been used {149,280,1562}.
Clinical features
As is the case with other heart tumours,
the presentation is varied, and depends
on location. Many cardiac lipomas are
incidental findings, or cause a variety of
arrhythmias, syncope and electrocardiographic abnormalities {342,638,1383,
1562,1735}. Rarely, outflow tract obstruction may occur {1869}. Computed
tomography and magnetic resonance
imaging may establish the fatty nature of
the tumour {1383}. Recurrences are rare
{2146}.
Imaging
The echocardiographic appearance of
cardiac lipomas varies with their location.
Lipomas in the pericardial space have
variable echogenecity but are often
hypoechogenic, while intracavitary lipomas are typically echogenic {66}. The
reason for this difference is unknown. At
echocardiography, intracavitary lipomas
are usually circumscribed but cannot be
differentiated from other circumscribed
cardiac masses. However, MRI and CT
both allow for very specific identification
of fat and therefore can be used to definitively diagnose lipomas {66}.
Histopathology
Similar to extracardiac lipomas, cardiac
lipomas are circumscribed masses of
mature adipocytes. Unusual histologic
variants of lipoma have not been
described in the heart, with the exception of pediatric cardiac lipoblastoma in a
child, which possessed immature and
mature adipocytes, with focal vascular
myxoid areas containing lipoblasts {500}.
Differential diagnosis
The main differential is lipomatous hypertrophy, a non-encapsulated lesion composed of mature fat and adipocytes
resembling brown fat cells intermixed
with enlarged cardiac myocytes occurring solely in the interatrial septum.
Lipomatous hypertrophy is most often an
incidental finding at autopsy, but may
uncommonly be the cause of unexplained atrial arrhythmias, congestive
heart failure, or superior vena cava
obstruction {242,365}.
The differential diagnosis also includes
the intramuscular variant of haemangioma, which may contain variable numbers of adipocytes.
Cardiac lipoma 271
Cystic tumour of atrioventricular node
Definition
Congenital multicystic tumour or rest
located at the base of the atrial septum in
the region of the atrioventricular node.
Lining cells may be derived from primitive endoderm.
ICD-O code
8454/0
Synonyms
Mesothelioma of atrioventricular node,
lymphangioma, endothelioma, inclusion
cyst, Tawarian node, benign mesothelioma of Mahaim, endodermal rest, congenital polycystic tumour of atrioventricular node, intracardiac endodermal heterotopia.
Epidemiology
The mean age at presentation is 38 years
(range birth- 78 years) and women are
more frequently affected than men
(approximately 3:1). One patient with
long standing heart block survived to
age 95, at which time the diagnosis was
made at autopsy {64}.
Etiology
Because most patients have a history of
congenital heart block, they likely are
congenital rests. In 10% of patients the
tumours occur in association with other
midline defects {240,1189,1617,1719,
2021}. The precise intrauterine migration
defect is unknown. The cell of origin is
foregut endoderm, not mesothelium as
previously believed. Because diagnosis
in advanced years occurs, the congenital nature is not proved in all. Evidence
that limited cell proliferation occurs in
some cases may explain presentation
later in life, and patients may live for
decades with complete heart block {64}.
Localization
By definition they occur adjacent to the
atrioventricular node. Similar lesions
have not been described elsewhere in
the body.
Clinical features
Two-thirds of patients present with complete heart block, 15% with lesser
degress of atrioventricular block, and
10% with sudden death without documented history of heart block {240}. The
remainder are incidental findings in newborns and infants with structural heart
defects. Only rarely are atrioventricular
nodal tumours detected in patients with
normal sinus rhythm. Most tumours have
first been diagnosed at autopsy but in
vivo diagnosis has been reported {102}.
Macroscopy
They range in size from 2-20 mm and are
multicystic, the cysts often barely perceptible.
Histopathology
They arise in the inferior interatrial septum and generally respect the boundaries of the central fibrous body, and do
not involve ventricular myocardium or the
272 Tumours of the heart - Cystic tumour of atrioventricular node
A.P. Burke
P.A. Araoz
valves. Tumour cells occur in nests or
line the variably sized cystic spaces.
Cells can interdigitate with myocytes
within the inferior septum, resulting in
degenerative changes within the
myocytes. Cells may be cuboidal, transitional, squamoid or show sebaceous differentiation. Multilayering may occur
along the cyst walls {240,1157,1189}.
Immunohistochemistry
The cells strongly express cytokeratin,
epithelial membrane antigen, carcinoembryonic antigen and B72.3. Cells may
also express calcitonin and serotonin.
{465,523,1173,1345}.
Electron microscopy
Two cells types are characteristic. Within
the solid nests, cells have well formed
basement membrane, cytoplasmic
tonofilaments and desmosomes. Cells
lining the spaces are also connected by
desmosomes, have short microvilli and
may contain electron dense material
{240}.
Prognosis
The tumours are benign neoplasms but
may result in significant arrythmias or
sudden death. Surgical excision has
been reported in a few patients
{951,1541}.
Cardiac sarcomas
Angiosarcoma
Definition
Angiosarcoma is a malignant tumour
whose cells display endothelial differentiation.
ICD-O code
9120/3
Synonyms
Haemangioendothelioma,
malignant
haemangioendothelioma,
haemangiosarcoma, haemangioendothelial sarcoma, malignant haemangioma and
malignant angioendothelioma {1179}.
Epidemiology
Angiosarcomas are the most common
malignant differentiated cardiac neoplasms {259,691}. They occur over a
wide age range (36 months to 80 years)
{259,1693} with a peak incidence in the
fourth decade. It occurs with equal frequency in men and women.
Localization
It most often arises in the right atrium
near the atrioventricular groove (80%),
but has been reported in the other three
chambers as well as in the pericardium
{921,1654}. Left atrial involvement is
unusual though it has been reported
{203,478,799}. In one series the right atrium was involved in 55.6% and showed
A
A.P. Burke
H. Tazelaar
J.W. Butany
D. El-Demellawy
R. Loire
T. Geva
F. Bonilla
J.R. Galvin
co-involvement of the right ventricle
(6.5%), pericardium (6.5%), and the left
atrium (0.9%) {1653}.
Clinical features
Signs and symptoms
Clinical features reflect location, size and
the extent of regional involvement, and
the presence or absence of metastases
{259}. Most are initially silent. Because of
frequent pericardial involvement {1653},
dyspnoea is not an early symptom as is
the case with other cardiac sarcomas.
The most common presenting symptom
is chest pain (46%) {259}. Right-sided
heart failure, often associated with hemopericardium and supraventricular arrhyth
mias are also frequent {1128A, 1398A}. A
significant number of patients present
with or have co-existent haemorrhagic
episodes, coagulopathy, anaemia, persistent haematomas or easy bruisability
{25}. Sometimes, early pericardial
involvement may lead to pericardial
biopsy during emergency surgical cardiac decompression for tamponade.
Cardiac rupture may occur, but is rare.
Presentation with lung metastases is not
uncommon {23,186,2216}. In 10% of
cases, fever, weight loss, and fatigue
remain unexplained for several months,
resulting in delayed diagnosis, large
tumour size, and advanced stage when
surgery is performed.
B
J.P. Veinot
R. Virmani
H. Kamiya
G. Watanabe
D. Grandmougin
M. Horimoto
H. Hiraga
The predominant right-sided location
allows for diagnosis by endomyocardial
biopsy, generally out of reach of other
sarcoma types (which have a predilection for the left atrium). Sometimes the
neoplasm remains undiagnosed in life
due to the absence of specific symptoms.
Imaging
At echocardiography angiosarcomas
typically appear as an echogenic, nodular or lobulated mass in the right atrium.
Pericardial effusion or direct pericardial
extension/invasion are frequently seen
{66}. At MRI angiosarcoma also usually
appears as a heterogeneous, nodular
mass in the right atrium. MRI imaging
sequences sensitive for hemorrhage (T1
weighted images) may show areas of
hemorrhage which may be diffuse or
nodular {65}. After administration of intravenous contrast (gadolinium-DTPA)
enhancement along vascular lakes may
be seen which has been described as a
“sunray” appearance {527}. Like echocardiography, MRI may also show pericardial effusion or direct pericardial invasion, though MRI is more sensitive than
echocardiography for distinguishing
between pericardial fluid and pericardial
tumour. CT findings are similar to the MRI
findings. CT usually shows a heterogeneous, nodular mass in the right atrium
C
Fig. 4.24 Cardiac angiosarcoma. A CT section at the level of the aortic valve demonstrates a soft tissue mass completely filling the right atrium. B Cardiac angiosarcoma arising in right atrioventricular groove, forming a papillary right atrial mass. Note the extensive pericardial involvement. C Metastatic angiosarcoma to the
lung, forming multiple haemorrhagic subpleural nodules (courtesy of Dr. William D. Edwards).
Cardiac sarcomas 273
A
B
Fig. 4.25 Cardiac angiosarcoma. A Cardiac angiosarcoma with papillary features. Serpiginous and gaping
vascular spaces lined by plump hyperchromatic endothelial cells. B Cardiac angiosarcoma with irregular
vascular spaces lined by atypical hyperchromatic, somewhat epithelioid endothelial cells.
with possible pericardial effusion or invasion. At CT angiosarcomas are usually
low attenuation due to necrosis but may
have focal high areas of attenuation due
to hemorrhage. CT may show a similar
pattern of contrast enhancement as MRI.
With MRI or CT, the presence of a hemorrhagic, irregular right atrial mass is
very suggestive of angiosarcoma, especially if accompanied by a pericardial
effusion {66}.
Macroscopy
Angiosarcomas usually form lobulated
variegated masses in the right atrial wall,
protruding into the chamber. They range
from 2.0 cm to several centimeters. The
masses are classically dark, grey-brown
to black in colour and may resemble a
melanoma {249}, but tumours with less
well-developed vascular spaces may
appear firm, yellow-white in colour, lacking the classic hemorrhagic appearance.
The pericardium is frequently involved
274 Tumours of the heart - Sarcomas
and hence a hemorrhagic pericardial
effusion is a frequent accompaniment.
While involvement of the tricuspid valve
and extension or invasion of the vena
cavae is reported, involvement of the pulmonary artery and interatrial septum are
unusual. In rare instances, the pericardium is the sole site of involvement.
Fig. 4.26 Epithelioid angiosarcoma. Note the prominent eosinophilic cytoplasm (arrows).
Histopathology
Over two-thirds of cardiac angiosarcomas are well to moderately differentiated
showing well-formed vascular channels
and papillary structures. The vascular
channels are irregular, anastomosing,
and sinusoidal. The lining cells are usually pleomorphic and atypical. They may
form cord-like structures in which lumina
are difficult to demonstrate. Mitoses are
usually present {249,259,590}. The
remaining third are poorly differentiated
and composed predominantly of
anaplastic spindle cells. In angiosarcoma with a focal or dominant spindle cell
pattern, poorly formed vascular channels
and extravascular red blood cells can
usually be identified focally. Generous
sampling may be necessary in order to
identify diagnostic areas in such cases
{249}. Often, metastatic as opposed to
primary lesions, show areas of better differentiation. Angiosarcoma with a solid
pattern of growth and individual cells
having epithelioid features have been
reported {2059}. In these cases the neoplastic cells have eosinophilic cytoplasm
with occasional cytoplasmic vacuoles.
The nuclei in this variety are usually
large, hyperchromatic and have prominent eosinophilic nucleoli. The stroma
can be abundant and hyalinized.
Immunoprofile
Immunohistochemical staining is important for the definitive diagnosis of vascular lesions, especially those with poorly
differentiated patterns in which vascular
channels are difficult to identify. Most
angiosarcomas express, to variable
degrees, usual endothelial cell antigens
including factor VIII (von Willebrand factor), CD31 and CD34. Of these, CD31
gives the most consistent results, has
good specificity and excellent sensitivity
(approximately
90%)
{462,2119}.
Vascular channels may be highlighted by
the use of laminin and type IV collagen.
Cytokeratin and epithelial membrane
antigen may be focally positive in conventional angiosarcoma and may be diffusely positive in epitheloid angiosarcomas {2247}.
Electron microscopy
With the wide availability of immunohistochemistry, ultrastructural study is less
critical for diagnosis. The classic ultrastructural feature of endothelial cells, the
Weibel-Palade body, is not demonstrable
Epithelioid
haemangioendothelioma
in most neoplastic cells. However,
pinocytotic vesicles, abundant intermediate filaments, and a moderate amount
of rough endoplasmic reticulum and
Golgi apparatus may be identified.
Pericytes may be demonstrated adjacent
to tumour cells {1291}.
Differential diagnosis
In cases with a dominant spindle cell pattern distinction from an unclassified spindle cell sarcoma, fibrosarcoma or malignant fibrous histiocytoma may be difficult. The detection of endothelial vacuoles or papillary structures are helpful.
Immunohistochemical stains for laminin,
type IV collagen and even reticulin stains
may help highlight the vascular lumina
{545}. The increasing incidence of
Kaposi sarcoma makes differentiation
from the spindle cell areas of angiosarcoma essential, though cardiac Kaposi
sarcoma is usually metastatic.
Pericardial angiosarcomas can be mistaken for mesotheliomas {1277} and
clumps of reactive mesothelial cells may
be trapped in areas of an angiosarcoma.
Stains for cytokeratin, calretinin, cytokeratin 5/6 and CD31 can help to differentiate the two populations of cells.
Genetics
Genetics studies involving cardiac
angiosarcomas are rare and they only
analyze isolated patients with heart primary tumours. Cytogenetic analyses of
cardiac angiosarcoma show no consistent chromosomal abnormality {590}. A
case of right atrial angiosarcoma demonstrated hyperdiploid clonal populations
with changes in chromosome number, as
follows: 55, XY, +der (1;17) (q10:q10),
+2,+7, +8, +19, +20, +21, +22, as well
as polysomy of chromosome 8 {2247}.
Other chromosomal changes reported
are gains of 5pter-p11, 8p12-qter,
20pter-q12 and losses of 4p, 7p15-pter-y
and abnormalities involving 22q
{310,590}. Molecular analyses on tumour
tissues have focused on genetic alterations of TP53 and K-ras. The few reports
available show that TP53 is more frequently altered than K-ras. Mutations of
the TP53 tumour suppressor gene have
been revealed by PCR-SSCP and
sequencing studies and by immunohistochemical staining in up to 50% of
tumours studied {662,1428,2247}. A Kras mutation has also been documented
in heart angiosarcoma {662}: a G-to-A
Fig. 4.27 Epithelioid haemangioendothelioma.
There are cords of tumor cells arranged circumferentially within a vessel wall. The cells show focal
vacuolization, representing intracytoplasmic vascular lumina.
transition at the first base of codon 13,
which resulted in one amino acid substitution (Gly-13-Ser), in 2 relatively young
patients (31 and 36 years old).
Prognosis and predictive factors
Cardiac angiosarcomas have an especially poor prognosis because they typically present in the face of advanced
disease {249}. In one study, 80% of
patients had metastatic disease at the
time of diagnosis and 90% survived less
than nine months {921}. A mean survival
of ten months after surgical excision, with
or without adjuvant therapy, has been
reported in another study {823}. In soft
tissue angiosarcomas, morphologic features that have statistically correlated
with poor outcome include age, large
size and high proliferative (Ki-67) index
{478,590}. Metastases occur most frequently to the lung (70%), then liver. No
significant correlation has been reported
between DNA ploidy patterns and clinical
outcome {590}.
Treatment
There are no randomized treatment trials,
but patients are generally treated by a
combination of surgery and radiation
with or without sarcoma-type chemotherapy. Surgical resection is necessary, but
complete excision cannot be achieved in
most cases, because lack of a dissection
plane and myocardial encroachment of
tumoural tissue. However, even partial
resection (with possible valve repair)
may provide some months of symptomfree survival. However, local recurrence
is the rule, even when resection was
thought to be complete. Heart transplantation has been used to treat cardiac
angiosarcoma, but without long-term survival {1654, 2043}.
Definition
Epithelioid haemangioendothelioma is a
vascular tumour composed of epithelioid
cells arranged in short strands or solid
nests. The constituent endothelial cells
are round or oval, contain small intracellular lumina, and frequently infiltrate muscular walls of vessels.
ICD-O code
9133/3
Epidemiology
Fewer than five have been reported in
the heart {26,249,1241}. Epithelioid haemangioendothelioma has been reported
in association with myelodysplastic syndrome {26}.
Histopathology
The intracellular lumens of epithelioid
haemangioendothelioma may mimic the
vacuoles of adenocarcinoma, which may
be initially considered in the microscopic
differential diagnosis. Immuno-histochemical stains for factor VIII-related
antigen, CD31, or CD34 identify the cells
as endothelial. The differential diagnosis
also includes epithelioid haemangioma,
a tumour even rarer as a cardiac primary
{453}.
Prognosis
Approximately 10% of extracardiac haemangioendotheliomas develop metastases, and up to one third recur. The biologic behaviour of epithelioid haemangioendotheliomas of the heart is
unknown. They should be considered
low-grade malignant, based on available
data on histologically similar extracardiac tumours, and a case report of a
tumour that developed distant metastases {1241}.
Epithelioid haemangioendothelioma 275
A
B
C
Fig. 4.28 Malignant fibrous histiocytoma. A Primary malignant fibrous histiocytoma with ossesous differentiation (osteosarcoma). B Malignant fibrous histiocytoma
with osseous differentiation (osteosarcoma). C Large nodules in the right atrium.
Pleomorphic malignant fibrous
histiocytoma (MFH) /
Undifferentiated pleomorphic
sarcoma
Definition
Malignant fibrous histiocytoma or undifferentiated plemorphic sarcoma is highgrade malignancy showing fibroblastic
or myobroblastic differentiation and
areas of marked cellular pleomorphism.
Malignant fibrous histiocytomas and
fibrosarcomas represent a broad spectrum of mesenchymal tumours and the
degree of cellular pleomorphism is the
major distinguishing feature.
ICD-O code
Malignant fibrous
histiocytoma
In a recent review, 81% of 47 cases were
left atrial {1508}. The other reported locations included the pericardial space (3
cases), right ventricle/ pulmonary valve
(3 cases), right atrium (1 case), and left
ventricle (1 case) {1508}. Although the
majority occur in the left atrium, where
they most often present like cardiac myxomas, they more commonly arise along
the posterior wall in comparison to the
septum {1056,1142,1526}.
A
B
8830/3
Synonym
Malignant fibrous histiocytoma is now
regarded as synonymous with undifferentiated pleomorphic sarcoma, as many
tumours formerly classified as MFH have
been found to have evidence of myogenic or other more specific differentiation.
C
D
Epidemiology
Malignant fibrous histiocytoma, as historically defined, is the second most common malignant cardiac sarcoma in adults
and, if considered with all undifferentiated sarcomas represents the most common sarcoma. There is no gender
predilection and the mean age is around
45 years (range, 20-80 years). Rare
cases have been reported in infants.
E
F
Localization
Malignant fibrous histiocytoma tends to
be located in the left atrium of the heart,
most commonly the posterior wall and /
or interatrial septum {1056,1142,1526}.
Fig. 4.29 Malignant fibrous histiocytoma (pleomorphic undifferentiated sarcoma). A In this example, there
is a myxoid background and a prominent vascular pattern reminiscent of myxoid malignant fibrous histiocytoma found in soft tissue. B Malignant fibrous histiocytoma arising in left atrium where it initially mimicked a cardiac myxoma. Note mitotic activity. C Note pleomorphic growth pattern. D Malignant fibrous
histiocytoma with osseous differentiation (osteosarcoma). Note formation of the mature bone trabeculae.
E Osteoid formation. F Cartilagenous differentiation.
276 Tumours of the heart - Sarcomas
Clinical features
Most occur on the left side of the heart
and cause signs and symptoms related
to pulmonary congestion, mitral stenosis
and pulmonary vein obstruction.
Tumours may also present with metastases and the lungs, lymph nodes, kidney and skin are common sites.
Constitutional signs and symptoms may
precede symptoms referable to the
heart. Diagnosis of cardiac sarcoma
rests on echocardiography; MRI is helpful preoperatively to determine precise
tumour size, location, and adjacent tissues invasion, and post-operatively for
assessment of excision and recurrence.
Macroscopy
Malignant fibrous histiocytoma typically
presents as a soft or firm polypoid endocardial based tumour. It may be sessile
or pedunculated, simulating myxoma,
but unlike myxoma, may form multiple
masses not obviously part of the same
tumour {1142}. The mass may distend
the atrium and impinge upon the mitral
valve. Extension into the pulmonary veins
and lung parenchyma may be present
{1056} They may be uniform tan-white or
variegated due to haemorrhage and
necrosis. Calcification is uncommon.
Histopathology
Malignant fibrous histiocytoma or undifferentiated pleomorphic sarcoma is a
diagnosis of exclusion, and immunohistochemical studies are important in ruling
out metastatic myogenic, melanocytic
and neurogenic tumours as well as sarcomatoid carcinomas. Of the subtypes of
malignant
fibrous
histiocytoma
described in the soft tissue, the pleomorphic (greater than 90%) and giant cell
subtypes have been recognized in the
heart. The tumours are heterogeneous in
appearance and are variably cellular.
The constituent cells may be spindled or
epithelioid and sometimes have abundant eosinophilic cytoplasm. Intermixed
giant cells are common. A storiform
arrangement of tumour cells is common
and they usually have marked pleomorphism. Mitotic activity is easy to find.
Osteosarcoma
Undifferentiated pleomorphic sarcomas
demonstrate areas of osseous differentiation in 15% of cases. There is debate as
to whether these tumours should be classified as extra skeletal osteosarcomas or
undifferentiated pleomorphic sarcomas
with osteosarcomatous differentiation.
Virtually all osteosarcomas of the heart
reported thus far have occurred in the left
atrium. Like skeletal osteosarcoma,
areas of malignant giant cell tumour
(giant cell malignant fibrous histiocytoma), chondroid differentiation, and
osseous differentiation have been found
to coexist in variable amounts in a single
lesion.
A
Genetics
Genetic studies of cardiac sarcomas are
limited. In studies of extra cardiac malignant fibrous histiocytoma, the common
signature of genetic alterations includes
recurring low-level copy number increases at new sites on chromosome 7, and
losses of chromosome 2 sequences
{1546}. Genomic imbalance at chromosome 13 has also been observed, with
high gains for Xp and bands 1q21-22,
1p31, 3q27 and 9q3. The losses at chromosome 13 were observed in a large
proportion at regions 13q12-14 and
13q21-22 {1131,1224}. Specific losses in
regions that harbour tumour suppressor
genes like INK4a (9p21) and RB1
(13q14) have been revealed by Southern
blot and comparative genomic hybridization {1828}. RB1 gene is probably implicated in tumourigenesis of malignant
fibrous histiocytoma due to the high correlation between absence of RB1 protein
expression and chromosome 13 losses
and mutations found in this gene {353}.
Mutations localized to the core domain of
TP53 have been found by immunohistochemical and sequencing procedures
{1982}, as have other abnormalities like
protein accumulation {1647}. TP53 mutations and accumulation of p53 protein
have been detected in tumours with
MDM2 gene amplification {1647}.
Treatment
Complete resection of malignant primary
cardiac tumours can rarely be achieved,
but palliative surgery is usually undertaken because many patients present with
mechanical obstruction {731}. Adjunctive
chemotherapy, radiation therapy or both
are sometimes used {731}, however, the
optimal protocol and efficacy are unclear
{731,1508,1962,2043}. Patients with
unresectable primary malignant cardiac
tumours who are free of metastases may
be considered for heart transplantation
{731,1962,2043}.
B
Fig. 4.30 A Myxosarcoma from the left atrium. Cut
surface showing variable solid, soft and haemorrhagic regions. B Fibromyxosarcoma. A portion of
the tumor near the endocardial surface shows an
undifferentiated spindle cell sarcoma without
prominent vascularity or pleomorphism and an
abundant proteoglycan matrix.
Prognosis and predictive factors
For malignant fibrous histiocytoma and
fibrosarcoma there is some evidence that
grading is useful in predicting survival,
but the majority of patients with these
tumours die of either local or metastatic
disease {731,952,1508}. The mean postoperative survival is 5-18 months. The
cause of death may be related to
metastatic disease, bulky intracardiac
recurrences, or general debilitation.
Fibrosarcoma and
myxosarcoma
Definition
Fibrosarcoma is a malignant tumour
composed of fibroblasts with variable
amounts of intercellular collagen and a
classic herringbone architecture. Some
fibrosarcomas with abundant myxoid
stroma have been called myxosarcomas
but are not considered malignant variants of cardiac myxoma. Tumours with
marked pleomorphism, or a prominent
vascular or storiform pattern are better
classified as malignant fibrous histiocytoma.
ICD-O code
Fibrosarcoma
8810/3
Fibrosarcoma / myxosarcoma 277
Epidemiology
Fibrosarcoma represents 5-10% of all
cardiac sarcomas depending on the criteria used for diagnosis. Fibrosarcomas
are less frequent, and occur over a
broader age range than malignant
fibrous histiocytoma, some having been
reported in children.
Localization
Fibrosarcomas are most common in the
left atrium, but have been reported to
arise in all chambers. Fibrosarcomas
may also infiltrate the pericardial space,
thus mimicking mesothelioma {1034}.
Clinical features
The clinical features of fibrosarcomas
have not been well-delineated from related cardiac sarcomas such as malignant
fibrous histiocytoma (undifferentiated
pleomorphic sarcoma) as the classification of these lesions has not been standardized in large series. As with other
sarcomas, signs and symptoms vary
depending on the location of the tumour.
Because most occur on the left side of
the heart, signs and symptoms related to
pulmonary congestion, mitral stenosis
and pulmonary vein obstruction are most
frequent. Rarely, cardiac fibrosarcoma
may present with metastases in the
lungs, lymph nodes, skin, and kidney.
Macroscopy
Fibrosarcoma typically presents as a soft
polypoid tumour projecting into the
chamber from whose walls they arise.
They have a gross appearance similar to
MFH {329}, but haemorrhage, necrosis,
and variegation are less common.
Histopathology
Fibrosarcoma of adult type is composed
of spindle shaped cells arranged in
sweeping fascicles that are often
arranged at angles to one another resulting in a “herringbone” pattern. The nuclei
are usually elongate with tapered ends
and darkly staining. Mitotic activity is
variable. In the myxoid variant tumour
cells spindling is less pronounced and
cells may take on a stellate or ovoid configuration. However in all types pleomorphism is minimal and prominent vascularity is absent.
Differential diagnosis
The differential diagnosis for the typical
variant of fibrosarcoma includes mono-
278 Tumours of the heart - Sarcomas
Fig. 4.31 Embryonal rhabdomyosarcoma predenting as small cell undifferentiated tumor with cellular areas
concentrated towards the surface.
phasic synovial sarcoma, inflammatory
myofibroblastic tumours and localized
fibrous tumours, and for the myxoid variant, other myxoid sarcomas (MFH,
leiomyosarcoma, etc.) and cardiac myxoma. The latter is generally distinguished
by the presence of myxoma cells, abundant organizing hemorrhage, and
absence of mitotic figures and high cellularity. Fibromas are easily distinguished
from typical fibrosarcoma by lack of cellularity and abundant collagen.
Prognosis and predictive factors
See discussion on treatment of maligant
fibrous histiocytoma. There is no proven
difference in prognosis between cardiac
fibrosarcoma and malignant fibrous histiocytoma as demonstrated in a metaanalysis using actuarial methods {249}.
Rhabdomyosarcoma
Definition
Rhabdomyosarcoma is a malignant
tumour with striated muscle differentiation.
ICD-O code
8900/3
Epidemiology
Rhabdomyosarcoma is a very rare subtype of cardiac sarcoma. In the past,
before immunohistochemical documentation of tumour histogenesis was routine,
it was stated that a large proportion of
cardiac sarcomas were rhabdomyosarcomas. However, in more recent series,
the proportion is less than 5% {250}, and
in one recent series of cardiac sarcomas
with rigorous immunohistochemical documentation, none of 24 was classified as
rhabdomyosarcoma {509}.
Localization
Rhabdomyosarcomas occur anywhere in
the heart. Approximately 50% occur in
the atria, and 50% in the ventricles. The
frequency of ventricular involvement is
greater than other cardiac sarcomas.
Contrary to sarcomas with fibro- or myofibroblastic differentiation, they are not
usually intracavitary tumours, but are
more often mural.
Fig. 4.32 Embryonal rhabdomyosarcoma with rhabdomyoblasts containing abundant eosinophilic
cytoplasm.
Clinical features
Cardiac rhabdomyosarcomas are usually of the embryonal variant and, there-
A
B
Fig. 4.33 Leiomyosarcoma. A The tumour is cellular, composed of fascicles of relatively uniform cells. B Note tumour cellularity and focal necrosis.
fore, occur most frequently in children
and young adults; it is the most common
primary cardiac malignancy in children.
The mean age at presentation is approximately 20 years, compared to 40-50
years of age for other subtypes of cardiac sarcoma. Rhabdomyosarcoma is
more likely than other primary cardiac
sarcomas to involve the valves. The clinical presentation, as with other cardiac
tumours, depends on the cardiac location.
genin greatly facilitates the diagnosis
{1630}. Desmin is also useful in documenting
muscular
differentiation.
Alveolar rhabdomyosarcoma, characterized by a collagenous stroma and a
paucity of rhabdomyoblasts, has been
described in the heart generally as a
metastatic lesion.Sarcoma botryoides,
with characteristic grape-like structures
and a so-called cambium layer, a form of
embryonal rhabdomyosarcoma, has also
been described in the heart {760}.
Macroscopy
Cardiac rhabdomyosarcomas are bulky,
invasive tumours that may be grossly
mucoid or gelatinous, similar to cardiac
myxoma, or soft and necrotic, with variegation and heterogeneity. They usually
arise within the myocardium and are less
likely than sarcomas with myofibroblastic
or fibroblastic differentiation to be endocardial based, luminal tumours.
Differential diagnosis
The differential diagnosis includes other
cardiac sarcomas, especially undifferentiated lesions and metastatic small round
cell tumours in children and young
adults. Immunohistochemical stains are
vital in identifying rhabdomyoblasts.
Adult cellular rhabdomyomas, in contrast
to rhabdomyosarcoma, lack significant
mitotic activity, necrosis, and do not
express myogenin.
Tumour spread and staging
Sites of metastatic spread are, in order of
descending frequency: lungs, regional
lymph nodes, central nervous system,
gastrointestinal tract, kidney, adrenals,
thyroid, ovary, bone and pancreas.
Histopathology
Cardiac rhabdomyosarcomas are almost
exclusively embryonal. Embryonal rhabdomyosarcoma is small cell neoplasm
with variable numbers of PAS-positive
rhabdomyoblasts (tadpole or strap
cells). Well-differentiated embryonal
rhabdomyosarcoma has numerous tadpole-shaped rhabdomyoblasts. Nuclear
staining with antibodies against myo-
Electron microscopy
The diagnostic features are thick and thin
filaments reminiscent of normal striated
muscle. Internal A and I banding may or
may not be present, but Z-bands are frequently well formed. Plentiful glycogen
granules and abundant mitochondria are
also present. Tumour nuclei are lobulated, containing variable amounts of condensed chromatin. Occasionally, several
grids must be examined before rhabdomyoblasts are identified.
Somatic genetics
At exon 1 of K-ras, a mutation at the first
base of codon 13 (G to A transition) has
been detected in cardiac rhabdomyosarcoma {662}.
Treatment
Surgery
Surgical resection of the tumour is usually indicated even if it is considered as
palliative to relieve obstruction to cardiac
blood flow and to clarify the diagnosis
{301,470,952}. Total orthotopic heart
transplantation may offer relatively longterm survival {67,701,733} if there are no
distant metastases.
Chemotherapy
Although the outcome of chemotherapy
on cardiac rhabdomyosarcoma has not
been fully studied, due to the rarity of the
tumour, there have been advances in the
treatment of soft tissue rhabdomyosarcoma {423,529, 1194,1749} with a threeyear progression-free survival of approximately 65%. Neoadjuvant chemotherapy
may optimize a surgical approach
{1749}.
Radiotherapy
Adjuvant radiotherapy is commonly
mandatory to preclude local relapse or to
optimize the results of a surgical
approach. However radiotherapy may be
used preoperatively to decrease tumor
size and allow surgical resection.
Prognosis and predictive factors
Specific prognostic microscopic features
have not been devised for cardiac rhabdomyosarcomas. However, grading is
similar for other subtypes of cardiac sarcomas, and includes an assessment of
mitotic activity and necrosis {509}. The
Rhabdomyosarcoma 279
A
B
Fig. 4.34 Synovial sarcoma. A The tumour is highly cellular and composed predominantly of spindled cells. The epithelial areas may be difficult to discern on routine stains. B Immunohistochemical stain demonstrating expression of pancytokeratin in islands of epithelial cells.
prognosis is poor, with recurrence and
eventual metastasis with death of the
patient within months the rule {1944}. The
mean survival rarely exceeds 12 months.
Leiomyosarcoma
Definition
A malignant tumour composed of cells
with distinct smooth muscle features.
ICD-O code
8890/3
Epidemiology
Cardiac leiomyosarcoma is uncommon,
representing less 10% of cardiac sarcomas. There is no sex predilection, and
most occur in patients between 40 and
50 years of age.
Clinical features
Dyspnoea is the main clinical feature.
Sometimes patients present with chest
pain, cough, atrial arrythmias, or haemoptysis.
Macroscopy
Most of them are located in the left atrium
(posterior wall) and invade pulmonary
veins or mitral valve. But, tumours can
arise elsewhere, including the right atrium and ventricle, or pulmonary valve or
trunk. The tumours tend to be firm, fleshy,
grey and sessile. They may present as
multiple intra-cavitary nodules.
oriented at sharp angle or 90° to one
another. Inconstant characteristic features include the presence of cytoplasmic glycogen and perinuclear vacuoles.
Pleomorphic and giant cells may be
present. Zones of necrosis and mitotic
figures are generally plentiful. Usual
immunohistochemical markers of neoplastic cells are smooth muscle alpha
actin and desmin. Alpha actin also
shows numerous normal little vessels in
the tumour tissue. There may occasionally be aberrant expression of cytokeratin
and epithelial membrane antigen.
Demonstration of smooth muscle cell
derivation virtually confirms malignancy,
as leiomyomas remain undescribed in
this location.
Treatment and prognosis
Treatment consists of surgical excision,
almost always incomplete. This may
allow some patients several months of
symptom free survival, typically less than
one year. Chemotherapy and radiation
therapy may provide palliation.
Synovial sarcoma
Definition
Synovial sarcoma is a biphasic tumour
composed of spindled and epithelioid
areas, characterized by X;18 chromosomal translocations.
ICD-O code
Histopathology
Leiomyosarcoma is composed of compact bundles of spindle cells that possess blunt-ended nuclei and are often
280 Tumours of the heart - Sarcomas
9040/3
Epidemiology
Synovial sarcomas account for approximately 5% of cardiac sarcomas {173,
300,400,1466}. The true incidence has
probably been underestimated, as
molecular studies can now confirm the
diagnosis in the monophasic variant,
which is the most common form in the
heart. An association between cardiac
synovial sarcoma and asbestos exposure has been reported {1144}.
Localization
There is a predilection for the atria and
pericardial surfaces.
Clinical features
Clinical symptoms may arise from
obstruction, embolism, and tamponade.
Macroscopy
Synovial sarcomas are bulky, infiltrative
tumours that are typically firm and white.
Necrosis or hemorrhage may be present.
Histopathology
The classic lesion is biphasic, but the
monomorphic variant is especially common in the heart. The spindle component
resembles a fibrosarcoma, but alternating
cellular and oedematous areas are typical. The spindle cells are small, compact,
and often infiltrated by sparse mononuclear lymphoid cells. The epithelioid cells
form clusters and nests, and occasionally larger gland–like spaces which may
show branching. Immunohistochemically,
cytokeratin and epithelial membrane antigen are strongly expressed in the epithelioid cells. Staining for these markers in
the spindle cells may be very focal.
Spindle cells express vimentin and occasionally smooth muscle actin. The cells
do not express CD34.
A
B
C
Fig. 4.35 Synovial sarcoma. A An example of detection of fusion SS18/SSX transcripts by RT-PCR. M; 1kb ladder, lane 1; a biphasic synovial sarcoma of soft tissue,
lane 2; a synovial sarcoma of peritoneum, lane 3; a malignant mesothelioma, lane 4; an adenocarcinoma of the lung. B Schematic diagram of domain structure of
the SS18, SSX, and SS18/SSX proteins. SNH (SS18 amino terminal domain) might act as a inhibitor of the QPGY domain, which is a C-Terminal domain rich in glutamine, proline, glycine and tyrosine and might function as a transcription activation domain. KRAB (kruppel-associated box) is a transcription repression domain.
However, the KRAB-like domain of SSX appears to be an inefficient or even inactive repressor domain. SSX-RD is a novel repressor domain, which is highly conserved in the SSX family. C Schematic representation of the translocation t(X;18)(p11.2;q11.2).
Differential diagnosis
Distinction of synovial sarcoma from
mesothelioma, another biphasic tumour,
can usually be made on the basis of
tumour location (mesotheliomas do not
occur within the atria) and growth pattern
(synovial sarcoma is usually a circumscribed solitary lesion while mesothelioma tends to grow diffusely over the
pericardium. Additionally, the spindle cell
areas of synovial sarcoma tend to be relatively monomophic. The X;18 translocation may be confirmed on formalin fixed,
paraffin embedded tissues and has a
high degree of sensitivity and specificity
{1506}. Reactivity for calretinin has been
described in both mesothelioma and synovial sarcoma, and is not helpful in the
differential diagnosis. Unlike mesothelioma, solitary fibrous tumour is generally
lower-grade, usually expresses CD34
antigen, is less cellular and tends to have
alternating hyper- and hypocellular areas.
Somatic genetics
Cytogenetically the reciprocal translocation t(X;18)(p11.2;q11.2) is seen in more
than 90% of soft tissue synovial sarcomas {1330}. This is considered to be the
primary cytogenetic abnormality and
specific for synovial sarcomas.
The breakpoints of the t(X;18) have been
cloned, and it has been shown that this
translocation results in fusion of SS18
gene (previously described as SYT or
SSXT) at the chromosome 18q11.2 to
either of two genes, SSX1 or SSX2, at
Xp11.2. This rearrangement of genes
produces a chimeric SS18 /SSX transcript, which could be implicated in
tumourigenesis {375}. The SS18/SSX
transcripts can be specific markers of
synovial sarcoma that can be detected
by the reverse transcriptase-polymerase
chain reaction (RT-PCR). The transcripts
can be identified in almost all synovial
sarcomas when there is adequate
tumour RNA {837}. This molecular diagnostic method also can be applied to
paraffin-embedded tissue {747}.
Synovial sarcoma 281
Cardiac lymphomas
Definition
Primary cardiac lymphoma (PCL) is an
extra-nodal lymphoma involving only the
heart and/or the pericardium. A less
restrictive definition includes small secondary lesions elsewhere, with the vast
bulk of the tumour arising in the heart. It
is clinically defined as a lymphoma presenting as cardiac disease with the bulk
of the tumour being intra-pericardial.
Cardiac involvement by disseminated
non-Hodgkin lymphoma should be
excluded.
Epidemiology
PCL is an uncommon malignancy,
accounting for 1.3% of primary cardiac
tumours and 0.5% of extranodal lymphomas {249,273,1679}. The published
series account for about 80 cases, while
cardiac involvement in disseminated
lymphoma has been documented in
nearly 20% of autopsy cases {1280}. The
appearance of PCL in patients with AIDS
{1736} and in a kidney recipient {1667}
suggests that immunodeficiency may be
Fig. 4.36 Cardiac lymphoma. Mulitofocal masses
involving both atria and ventricular walls.
282 Tumours of the heart - Lymphomas
G. Rolla
F. Calligaris-Cappio
A.P. Burke
a predisposing factor. However, the heart
is an uncommon site for immunodeficiency-related lymphoma. Most PCL arise in
immunocompetent patients. The median
age of the reported cases is 62 years
(range, 5-90 years) with a male-to-female
ratio of 3:1.
The clinical course is generally short,
with a mean survival of 7 months (range,
0-48 months).
Clinical features
Signs and symptoms
The clinical course is generally acute in
onset. There is no pathognomonic clinical presentation and patients are generally investigated because of chest pain,
pericardial effusion, refractory heart failure, arrhythmia, or lightheadness and
syncope due to a myxoma-like intracavitary mass {308}. Superior vena cava
obstruction {363}, multiple pulmonary
emboli and infarction {1832} and hypertrophic cardiomyopathy {266} have also
been reported as initial diagnosis in
patients with PCL. Complete atrio-ventricular block may be the major clinical
presentation {1416}.
Imaging
Because the gross pathologic features of
primary cardiac lymphoma are variable,
the imaging findings are variable.
Cardiac lymphomas most commonly
manifest as circumscribed, nodular
masses in the myocardium, often with an
associated pericardial effusion. These
findings are usually well seen at echocardiography, MRI, and CT. Lymphoma may
also manifest as an ill-defined, infiltrative
mass, in which case, they are typically
best depicted with MRI because of its
superior soft tissue contrast {66}. Internal
imaging features and contrast enhancement patterns are very variable with cardiac lymphomas. Lymphomas may have
high or low signal on MRI, may have similar attenuation as muscle or lower attenuation than muscle on CT, and may show
increased, or decreased contrast
enhancement. In some cases, pericardial effusion or pericardial thickening
may be the only findings. In additon to
echocardiography, MRI, and CT, nuclear
medicine techniques may be useful procedures for the non-invasive assessment
of cardiac lymphomas. Gallium-67
uptake is non-specific, though a marked
accumulation in the heart without extracardiac uptake can suggest the diagnosis
of PCL {1680}.
Diagnostic approach
When pericardial effusion is present its
drainage may have both palliative and
diagnostic purposes. Lymphoma cells
may be detected in serous fluid in up to
88% of cases {308}.
When cytology is not available, the diagnosis of PCL is usually assessed by
explorative thoracotomy with cardiac
mass biopsy. Recently, less invasive procedures have been performed, such as
transoesophageal echocardiography
(TEE) guided percutaneous intracardiac
biopsy {46,947}.
Macroscopy
PCL may arise in either atrium or ventricle. Usually the tumour is large, infiltrating myocardium and extending into the
right atrium and ventricle in the form of
multiple intracavitary polypoid nodules,
which may eventually obliterate the cavities. The right atrium is involved in more
than 2/3 of patients. The pericardium is
usually thickened by white-greyish
tumour infiltration. Pericardial effusion,
which is generally massive, may be isolated (12.5% of cases) or associated with
a heart mass (near half of cases) {737}.
Cytology
A diagnostic cytologic sample sample is
obtained in less than 20% of primary cardiac lymphomas (PCL) {1680}. It may be
difficult to differentiate PCL from benign
reactive lymphocytosis by cytology
alone. Immunocytochemical staining
{1724}, cytogenetic studies {1} and polymerase chain reaction {964} have been
performed successfully to confirm the
lymphoid lineage and detect the presence of a monoclonal population.
A
B
C
Fig. 4.37 Cardiac lymphomas. A Mass limited to the myocardium in a 40-year old man. Tumour cells are moderately sized with high mitotic rate; immunophenotype
was consistent with diffuse large B-cell lymphoma. B In this example of a localized left ventricular tumour, the lymphoma cells are large and irregular.
Immunophenotypically, the tumour typed as a diffuse large B-cell lymphoma. C Occasionally, cardiac lymphomas are of the high-grade small cell type (lymphoblastic lymphoma). In this lesion, the immunophenotype confirmed B-cell Burkitt subtype.
Histopathology
Diffuse large B-cell lymphoma is the subtype most frequently observed (80% of
published cases). Non-cleaved small
cell lymphoma has been reported in a
few cases; the histopathology was
unspecified in the other cases. Recently
two cases of diffuse large B-cell lymphoma with CD5 expression have been
reported {317}. This is a recently identified subgroup of diffuse large B-cell lymphomas, which differs for clinical characteristics (elderly, female and extranodal
involvement) and aggressive clinical
course {2181}. One case of Burkitt lymphoma in an immunocompetent patient
has been described {317}.
Somatic genetics
A complex abnormal karyotype containing t(8;14) (q24;q32) has been reported
in a case of diffuse large B-cell lymphoma mainly involving the heart with
cells which were CD5+ and CD20+ with
a c-myc rearrangement {1948}. In situ
hybridization for EBER-1 was negative.
response (mean follow-up 17 months;
range 3-40 months). PCL should be
treated like other aggressive lymphomas
arising in other primary sites.
Prognosis and predictive factors
Late diagnosis appears to be a major
factor in the poor outcome in PCL
patients. Irrespective of the treatment
applied, 60% of the patients died of their
tumour 1.8 months after diagnosis {317}.
Prompt anthracycline-based chemotherapy results in near 60% of complete
Cardiac lymphomas 283
Metastatic tumours to the heart
Definition
Malignant cardiac neoplasm with a nonpericardial or myocardial primary site.
Metastatic tumors that infiltrate myocardium are frequently accompanied by pericardial metastases, especially in the
cases of carcinomas, which additionally
involve mediastinal lymph nodes.
Epidemiology
In a series of 133 surgically resected cardiac tumors, 14% were metastatic
{1411}. In a recent review, cardiac
metastases were present in 12% of
autopsies performed for widespread
malignancy {12}. Primary tumors in
decreasing order of frequency include
carcinomas of the lung, lymphomas, carcinomas of the breast, leukemia, carcinomas of the stomach, malignant
melanoma, hepatocellular carcinoma
and carcinomas of the colon. The following tumors have an especially high rate
of cardiac metastasis if the incidence of
the primary tumor is considered:
leukemia, melanoma, thyroid carcinoma,
extracardiac sarcomas, lymphomas,
renal cell carcinomas, carcinomas of the
lung and carcinomas of the breast.
These tumors all had a greater than 15%
rate of cardiac metastasis in a large
autopsy study {1398}.
The rate of cardiac involvement by
metastatic disease has not appeared to
change over a 14-year period, indicating
that current treatment modalities may not
have a significant effect on the rate of
metastatic malignancy to the heart.
tumor; haematogenously; via lymphatics;
and rarely by intracavitary extension from
the inferior vena cava or pulmonary
veins. Lymphatic spread is generally
accompanied by involvement and
enlargement of pulmonary hilar or mediastinal lymph nodes. Haematogenous
spread is characterized by myocardial
involvement.
Epithelial malignancies typically spread
to the heart by lymphatics. Melanoma,
sarcomas, leukemia and renal cell carcinoma metastasize to the heart by a
haematogenous route. Melanomas, renal
tumours, including Wilms’ tumour and
renal cell carcinoma, adrenal tumours,
liver tumours, and uterine tumours are
the most frequent intracavitary tumours.
Metastatic cardiac tumours affect the
right side of the heart in 20-30% of
cases, the left side in 10-33% of cases,
and show bilateral or diffuse involvement
in approximately 30-35% of cases. The
endocardium or chamber cavities are
involved in 5% of cases {1398}. The most
common epithelial malignancies to
metastasize to the heart are carcinomas
of the breast and lung. In most cases
there is pericardial involvement with
superficial myocardial infiltration. The
valves and endocardium are usually
spared. Generally, the heart is not the
only organ involved, and metastatic
deposits are usually present in extracardiac sites.
The myocardium is involved in virtually
100% of cases of metastatic melanoma,
Clinical features
The cardiac location of the tumor greatly
affects the signs and symptoms. These
can include symptoms related pericardial effusions, arrhythmias, or congestive
heart failure. Obstruction of the mitral or
aortic valve may cause syncope. Involvement of the right heart and tricuspid
valves may give rise to right-sided failure.
Localization
Malignancies spread to the heart by
direct extension, usually from mediastinal
Fig. 4.38 Metastases of a large cell carcinoma of
the lung in the heart.
284 Tumours of the heart - Secondary tumours
G. Rolla
F. Calligaris-Cappio
and there is less frequent infiltration of
epi- and endocardium.
Leukemic and lymphomatous infiltrates
are typically widespread, involving the
epicardium (61%), and myocardium diffusely. The left ventricle is involved in
55%, and right atrium in 54% of cases.
Sarcomatous deposits are found within
the myocardium (50%), pericardium
(33%), or both myocardium and pericardium (17% of cases). Valvular metastases
are
uncommon
{764}.
Osteosarcoma, liposarcoma, leiomyosarcoma, unclassifiable sarcomas, rhabdomyosarcoma, neurofibrosarcoma, synovial sarcoma, and maligant fibrous histiocytoma have been reported to involve
the heart secondarily.
Pathologic findings
Metastatic deposits may be diffuse,
multinodular, or consist of a single dominant mass. Especially with carcinomas,
there may be diffuse studding and thickening of the pericardial surfaces. This
pattern can grossly be confused with
mesothelioma, or benign fibrosing pericarditis. The tumour burden in the heart
is the highest with melanoma, as compared to any other malignancy.
Carcinomatous spread in the myocardium is frequently most prominent in
subepicardial lymphatics, whereas
melanomas, sarcomas, renal cell carcinomas and lymphoid neoplasms form
intramyocardial interstitial tumours. The
histopathologic distinction between primary and metastatic sarcoma may be
impossible upon surgical resection of a
cardiac tumour. Most sarcomas metastatic to the heart cause symptoms at their
primary site before cardiac symptoms
are evident, however {764}. Although primary sarcomas of the heart are uncommon, extracardiac sarcomas presenting
as cardiac metastases are even rarer.
Pericardial tumours
Solitary fibrous tumour
Definition
An uncommon, spindle-cell, fibroblastic
tumour which often shows a prominent
haemangiopericytoma-like vascular pattern.
ICD-O code
Solitary fibrous tumour
8815/1
Synonyms
Benign mesothelioma, fibrous mesothelioma, submesothelial fibroma
Localization
The most common locations, outside the
pleura, include the head and neck, especially orbit, soft tissue, especially
abdomen, extremities, and meninges
{233,1384,1473}. As with any lesion common to the pleura, there have been
examples of solitary fibrous tumour
reported in the pericardium and rarely
within the heart.
Clinical features
Clinical features are related to pericardial
mass effect.
Macroscopy
Solitary fibrous tumours tend to be wellcircumscribed, firm, fleshy or white
A. Burke
R. Loire
R. Virmani
although diffuse mesothelial surface
involvement has been described.
Histopathology
Histologic variability is the rule and multiple growth patterns have been described.
Most tumours will have a predominant
monomorphic spindle cell pattern resembling low-grade fibrosarcoma although
broad tumour cell fascicles are rare.
Areas of hypercellularity typically alternate
with those that are less cellular. The less
cellular areas can by myxoid or contain
abundant collagen {459}. Typically the
nuclei of tumour cells are closely apposed
to collagen bundles. A haemangiopericytoma-like vascular pattern may be conspicuous, present in a small portion of the
lesion, or absent. The differential diagnosis includes other monomorphic spindle
cell tumours, including neurogenic
tumours, spindle cell mesotheliomas,
monophasic synovial sarcoma, and
fibrosarcoma {1311}. Recently, desmoid
tumour of the pleura has been added in
the list of differential diagnostic considerations {2151}. See pleural section for
additional information.
Immunoprofile
Solitary fibrous tumours are CD34 and
bcl-2 positive. They are consistently negative for epithelial markers, muscle spe-
A
B
Fig. 4.39 Mesothelioma of pericardium. A Note the
extensive tumour encasing the pericardium. B In
many cases, the pericardial mass is in continuity
with pleural mesothelioma.
cific actin, desmin, CD31, CD117 (c-kit),
S-100 protein calretinin, and inhibin
{596,772,1473,2127}.
Differential diagnosis
Sarcomatous mesotheliomas of the pericardium are distinguished from solitary
fibrous tumours by their diffuse growth
pattern, and keratin and calretinin reactivity. On the other hand, solitary fibrous
tumour may closely mimic monophasic
synovial sarcoma and low- grade
fibrosarcoma. Fibrosarcoma tends to be
more architecturally monomorphic and
negative for CD34. Monophasic synovial
sarcoma has higher grade cytology,
plumper nuclei and shows focal keratin
reactivity. Endometrial stromal sarcoma,
and metastatic granulosa cell tumour
may be excluded by negative reactivity
for cytokeratin, estrogen and progesterone receptors, and inhibin.
Fig. 4.40 Localized fibrous tumor of the mesothelium is identical in appearance to those of the pleura. Note
the spindle cell growth with prominent vascularity and variable cellularity.
Solitary fibrous tumour 285
A
B
C
Fig. 4.41 Pericardial mesothelioma. A The majority of pericardial mesotheliomas are epithelioid. B Strong expression of calretinin. C Strong expression of cytokeratin 7.
Prognosis and predictive factors
The prognosis is generally good,
although recurrences and local spread
have been reported. Criteria for malignancy of pleural tumours include necrosis and a mitotic count of greater than 4
per 10 high powered fields, but the applicability of these criteria to tumours in the
heart and pericardium is unknown.
Malignant mesothelioma
Definition
Malignant mesothelioma arises from
mesothelial cells or demonstrates
mesothelial differentiation. The definition
of primary pericardial mesothelioma stipulates that there is no tumour present
outside the pericardium, with the exception of lymph node metastases.
ICD-O code
9050/3
Epidemiology
Mesothelioma of the pericardium represents approximately 0.7% of malignant
mesotheliomas {831}. As with mesotheliomas in other sites, the incidence may
be increasing, due to the latency
between asbestos exposure and tumour
development {1074}.
Etiology
Like pleural mesotheliomas, a large proportion of mesotheliomas of the pericardium are induced by asbestos {1074}.
Iatrogenically
induced
pericardial
mesotheliomas have been reported
decades after exposure to pericardial
dusting with asbestos and fibreglass as
a treatment for angina pectoris.
Therapeutic radiation for breast cancer
and mediastinal lymphoma has also
been implicated in rare patients.
However, there remains a subset of
286 Pericardial tumours
patients with mesothelioma who have no
known exposure history.
Clinical features
Signs and symptoms
The mean age of patients with pericardial
mesothelioma is about 45 years, with a
wide age range, including elderly, older
children and young adults. The initial
course is usually related to pericardial
effusions. Tamponade may eventually
occur {1202}.
Imaging
Echocardiography usually shows pericardial effusions and may show pericardial thickening. However, because pericardium is at the periphery of the field of
view obtainable with echocardiography,
MRI or CT are usually necessary. MRI
and CT usually demonstrate pericardial
fluid as well as pericardial thickening
and/or pericardial masses {737}.
Macroscopy
Malignant mesotheliomas of the pericardium can form bulky nodules that fill
the pericardial cavity. The tumour can
also spread diffusely over the pericardial
surface and completely encase the
heart. They can further encircle the great
vessels and may obstruct the venae
cavae.
Histopathology
Malignant mesotheliomas of the pericardium resemble pleural mesotheliomas. Although the majority are of the
epithelioid type, forming tubules, papillary structures, and cords of infiltrating
cells that can incite a desmoplastic
response, the sarcomatous variant is
also common. Variants similar to those
described in the pleura may also be seen
in the pericardium e.g. microcystic, adenomatoid, deciduoid {1649,1802}.
Immunoprofile
The immunohistochemical profile of pericardial mesothelioma is similar to that of
pleural mesothelioma. Expression of
mesothelial antigens, such as calretinin,
and cytokeratins 5/6 are helpful in the
diagnosis, as are negative reactions for
adenocarcinoma markers, such as carcinoembryonic antigen.
Electron microscopy
Ultrastructurally, mesothelioma cells from
epithelioid areas contain branched,
bushy microvilli. Cytoplasmic tonofibrils
are present in approximately 50% of
tumours. Asbestos bodies may be identified within pericardial mesothelioma, but
are of no diagnostic utility.
Differential diagnosis
The distinction between mesothelioma
and pleural-based lung adenocarcinoma
can be quite difficult, and is generally
based on immunohistochemical findings.
Distinction from reactive mesothelial cell
proliferations may also be difficult; in
comparison to reactive pleural mesothelial proliferations, reactive pericardial
mesothelial cells may be more deeply
“invasive”. Reactive stromal cells may
also often attain bizarre and pleomorphic
shapes, confusing the histopathologic
picture. Other malignancies that may be
confused with mesothelioma include
pericardial-based angiosarcoma, which
may elicit a prominent mesothelial
response, malignant solitary fibrous
tumour
and
synovial
sarcoma.
Immunohistochemistry is invaluable in
such circumstances. Mesothelioma lacks
the X;18 translocation of synovial sarcoma.
Prognosis and predictive factors
The prognosis of pericardial mesothelioma is poor. Fifty per cent of patients
ed, over 90% within the pericardium, and
the remainder in the myocardium. The
majority are pericardial teratomas {248},
and the remainder are yolk sac tumours
{411,1178}. Reports of intrapericardial
teratoma describing the presence of only
one or two germ cell layers may represent misclassified bronchogenic cysts.
Fig. 4.42 Pericardial teratoma. T1-weighted spin
echo MR image in the coronal plane showing large
pericardial teratoma (T). The right atrium (RA) is
compressed by the tumour.
survive 6 months, and an exceptional
patient may live as long as 48 months
{248}.
Germ cell tumours
Definition
A neoplasm of germ cell origin classified
by histologic type into seminoma (dysgerminoma), embryonal carcinoma, yolk
sac tumour (endodermal sinus tumour),
choriocarcinoma, and teratoma.
Epidemiology
Approximately 100 cases of intrapericardial germ cell tumours have been report-
Clinical features
Patient age ranges from intrauterine life
to 66 years {411}. Teratomas generally
occur in infants while adults tend to have
malignant germ cell tumours. Over 75%
of cardiac teratomas occur in children
under age 15. There is a slight female
predominance. Symptoms include respiratory distress, pericardial tamponade,
and cyanosis. Occasionally mediastinal
teratomas in adults may secondarily
involve the pericardium.
Due to the routine use of fetal echocardiography, an increasing number of pericardial teratomas are being diagnosed in
second and third trimester fetuses {1615,
1786,2005}. Neonates may die at birth
from cardiac tamponade and cardiac
compression. Prenatal resection and
intrauterine pericardiocentesis have
been successfully accomplished {1615,
1935}.
Intramyocardial
teratomas
have
occurred in the newborn period or in the
first 6 years of life {1615}. Most patients
are symptomatic and present with congestive heart failure; rarely, a patient may
be asymptomatic, or sudden death may
be the first symptom, due to acute
arrhythmia caused from the tumour’s
interventricular location.
Macroscopy
Cardiac teratomas may be massive,
measuring up to 15 cm. They have a
smooth surface and are lobulated. The
tumours are multicystic with intervening
solid areas. The tumours usually displace the heart and rotate it along its longitudinal axis. Intrapericardial teratomas
are usually located on the right side of
the heart, displacing the organs to the
left and posteriorly; those located on the
left side will produce the opposite effect.
Teratomas are usually attached by a
pedicle to one of the great vessels with
arterial supply directly from the aorta.
Histopathology
Teratomas of the heart are similar to
extracardiac teratomas. A minority of
germ cell tumours of the pericardium are
yolk sac tumours {248,411,1792}.
Histogenesis
The cell of origin of extragonadal teratoma, including pericardial teratoma, is
the primordial germ cell. Although normal germ cells migrate from the yolk sac
to the gonad, they may lodge early in
embryogenesis in midline structures
such as the mediastinum.
Treatment
Surgical excision is the only effective
treatment for cardiac teratoma. Since the
blood supply is usually from the root of
the ascending aorta, the surgeon must
perform a careful dissection and ligation
of these vessels to prevent massive hemorrhage.
Intracardiac
teratomas,
because of their location in the interventricular septum, are more difficult to
remove than pericardial teratomas.
Malignant germ cell tumours require
standard chemotherapy.
Metastatic pericardial tumours
Fig. 4.43 Yolk sac tumour. The patient was a young woman with a pericardial mass, detected incidentally.
A high percentage of pericardial biopsies occur in patients in whom the diagnosis of malignancy has not yet been
made, either for life-threatening tamponade or to establish the cause of pericarditis {1201,1499}. In about two-thirds
of patients with positive pericardial biopsy, the clinical diagnosis is pericarditis,
Germ cell tumours 287
Table 4.03
Malignant tumours diagnosed at pericardial biopsy
{1201}.
Tumour type
Number
Fraction
Carcinoma
Adenocarcinoma
Squamous cell
Large cell
Small cell
Lymphoma
Sarcoma
MFH
Angiosarcoma
Leiomyosarcoma
Neurofibrosarcoma
Thymoma
Melanoma
54
32
14
7
1
12
7
3
2
1
68%
40%
18%
9%
1%
15%
9%
3%
2%
1%
5
2
6%
2%
Total
80
100%
and in the remainder, tamponade. False
negative biopsies may occur due to sampling, and it is not uncommon to have a
positive cytology and a negative biopsy.
Most adenocarcinomas presenting as
pericardial metastases originate either in
288 Tumours of the heart
the lung or an undetermined primary site.
Breast carcinoma, unlike lung carcinoma,
usually manifests as pericardial disease
only after the primary site is known. Other
tumours found in pericardial biopsies
include lymphoma, melanoma, multiple
myeloma, thymoma, metastatic seminoma {121,249,1398}. The sites of origin of
tumours discovered initially at pericardial
biopsy are shown in Table 4.03.
The distinction between reactive
mesothelial hyperplasia and metastatic
carcinoma can be difficult, and is assisted by immunohistochemistry. The presence of carcinoembryonic antigen,
berEP4, B72.3 antigen, and Leu M1
favour carcinoma over mesothelial
hyperplasia. Calretinin and cytokeratin
5/6 reactivity favour the diagnosis of a
mesothelial process.
The treatment of malignant pericardial
disease includes establishing a pericardial window, sclerosis with tetracycline or
other agents, and radiation therapy
{1069}. Malignant pericardial effusions
are generally a sign of rapidly progressive disease, necessitating emergency
treatment. Patients with metastatic pericardial disease have a mean survival of
4.3 months {1201}. In contrast, patients
Fig. 4.44 Metastatic pericardial tumors. Gross large
metastatic nodules in cardiac chambers and
myocardium (renal cell carcinoma).
with pericardial malignant lymphoma or
with involvement by thymoma often fare
significantly better.